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HK1171036B - Template-fixed peptidomimetics with ccr10 antagonistic activity - Google Patents

Template-fixed peptidomimetics with ccr10 antagonistic activity Download PDF

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HK1171036B
HK1171036B HK12111862.8A HK12111862A HK1171036B HK 1171036 B HK1171036 B HK 1171036B HK 12111862 A HK12111862 A HK 12111862A HK 1171036 B HK1171036 B HK 1171036B
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Hong Kong
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trp
dab
pro
cyclo
cyp
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HK12111862.8A
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HK1171036A (en
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F．荣
F．O．贡贝尔
D．奥伯莱希特
C．比桑
S．巴泰勒米
A．勒德雷尔
E.舍瓦利耶
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波利弗尔股份公司
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Description

Template-immobilized peptidomimetics having CCR10 antagonistic activity
The present invention provides a peptidomimetic in which a chain of 4 α -amino acid residues as defined below is incorporated, the peptidomimetic being attached to a template which provides specific structural constraints of a β -hairpin-like conformation. These template-immobilized β -hairpin mimetics have antagonistic activity against the CCR10 receptor and are therefore useful for the treatment of a variety of diseases and disorders, such as inflammatory skin diseases, allergic asthma, gastrointestinal/colonic diseases, certain melanomas, cutaneous lymphomas, or other conditions mediated or maintained by the activity of CCR 10. The invention also relates to methods of using these compounds in the treatment of various diseases and disorders as described above, to pharmaceutical compositions and forms comprising these compounds, and to efficient processes for preparing and producing these compounds and their intermediates.
Many medically relevant biological processes are mediated by signal transduction involving chemokines and their receptors, for example, tissue-specific recruitment of leukocytes to inflammatory sites. In blood there is a subset of memory T cells, morphologically characterized by expression of skin lymphocyte antigens (CLA), which preferentially home to dermal endothelial cells and associated tissues. Recent studies have shown that CLA+Memory T cells also express the chemokine receptor CCR10, and in addition, the specific ligand for this receptor CCL27 was significantly upregulated in tissues detectably enriched in cells expressing these CCR 10. This indicates that CCR10/CCL27 interacts in CLA+Memory T cells are of great interest in tissue-specific trafficking, e.g., to inflammatory tissue injury. Except in CLA+In addition to on T cells, CCR10 has also been shown to be expressed in melanocytes, dermal fibroblasts, skin keratinocytes, microvascular endothelial cells, langerhans cells and certain types of tissue such as human heart or colon. Abundant CC was observed on the epidermisExpression of L27 (expressed primarily by keratinocytes), which is tightly regulated by proinflammatory mediators such as TNF- α and IL-1 β, CCL27, although expressed in keratinocytes, has a high affinity for extracellular matrix proteins and, therefore, is also presented on skin vascular epidermal cells following extracellular diffusion to participate in leukocyte repression.
More and more studies provide evidence that: the CCR10/CCL27 interaction has a role in the migration and localization of subsets of T cells during physiological responses in inflammatory or infected skin or mucosal tissue (J.Morales et al, Proc.Nat.Acad.Sci.,1999,96, 14470-. In pathological conditions such as psoriasis, atopic dermatitis or graft versus host disease, CCL27 expression was found to be significantly upregulated relative to normal skin or tissue biopsies. Thus, recruited CCR10 can be observed+Significant accumulation of lymphocytes (B. Homey, Current Drug Targets-infection)&Allergy,2004,3, 169-. The same effect was observed in nickel-allergic persons after stimulation of the skin with nickel. In two separate in vivo proof-of-concept studies (using DNFB induction and ovalbumin DTH models in wild type mice, respectively), the same authors showed: leukocyte recruitment decreased significantly following treatment with a functional blocking antibody to CCL27, with lower swelling.
More recent findings strongly suggest: another ligand/receptor interaction of CCR10 (interaction with the mucosa-bound epithelial chemokine CCL28) has a significant contribution to the pathogenesis of inflammatory respiratory and skin diseases, as demonstrated by allergic asthma in murine models and atopic dermatitis in children (b.p. mahon, Immunology Letters,2006,103,92-100; m.h. m.ezzat et al, int.j.of Dermatology,2009,48,822-829; a.zlotnik et al, j.of biological. chem.,2000,275, 22313-22323).
Our studies in this area indicate that expression of CCR10 is increased up to 800-fold in melanoma samples compared to healthy skin based on RNA quantification. This resulted not only in an advantage in the growth of mouse B16 melanoma cells, but also in a significant increase in metastasis to draining lymph nodes, compared to B16 cells that did not express CCR 10. In vitro, activation of CCR10 by CCL27 results in activation of PI3K, with an overall downstream effect of protecting B16 cells expressing CCR10 from tumor-specific cytotoxic T cells (T. murakami et al, j.exp.med.,2003,198, 1337-.
Proof of concept studies, such as those described above, highly recommend transmembrane G-protein coupled receptor (GPCR) CCR10 as a target for the treatment of a variety of disease conditions. Although nearly 350 GPCR receptor-targeting therapeutics have been successfully marketed in the past 15 years (th. klabunde, g. hessler, chem biochem 2002,3,928-44; g. vauquelin et al. fundam. clin. pharmacol.2005,19,45-56), there is still a need to address several toxicological issues, mainly due to the lack of selectivity of some of those drugs. Clearly, there is a need for different concepts in designing these agents to address the current problems and to produce effective and safe drugs for treating or preventing diseases or conditions associated with the target.
The present invention provides novel chemical entities that are potentially useful as potent, selective and pharmaceutically useful ligands for the GPC receptor CCR 10. In the compounds described below, a novel strategy was employed to stabilize the β -hairpin conformation in a backbone cyclic peptidomimetic which exhibits selective antagonist activity against the CCR10 receptor. This involves grafting the loop sequence of the natural or non-natural biopolymer onto a template that functions to constrain the peptide loop backbone to a hairpin shape.
Hairpin peptidomimetics (D, Obrecht, M. Altorfer, J.A.Robinson, adv.Med.Chem.1999,4,1-68; J.A.Robinson, Syn.Lett.2000,4,429-441) that bind to a template have been described in the literature, and means for producing beta-hairpin peptidomimetics using combinatorial and parallel synthesis methods (L.Jiang, K.Moehle, B.Dhanapaal, D.Obrecht, J.A.Robinson, Helv.Chim.acta.2000,83,3097-3112) have been established. These methods enable the synthesis and screening of large libraries of hairpin mimetics, which in turn significantly facilitates structure-activity studies, thus facilitating the discovery of new molecules with potent, in particular selective agonistic or antagonistic activity.
Very few studies in the art have described template-linked tetrapeptides as agonists and/or antagonists of GPCRs, particularly CCR10 (WO 2008092281). The present invention now provides alternative novel compounds which differ significantly in structure, surprisingly showing substantial improvement in key pharmaceutical parameters such as biological potency, stability or selectivity.
The beta-hairpin peptidomimetics obtained by the methods described herein are useful as antagonists of CCR10 and thus as chemotherapeutic agents for e.g. psoriasis, atopic dermatitis, contact and allergic dermatitis, stevens-johnson syndrome, bullous skin diseases, systemic lupus erythematosus, systemic and multiple sclerosis, allergic asthma, arthritis, graft versus host disease, certain melanomas and cutaneous lymphomas, thyroiditis, and inflammatory processes of the gastrointestinal tract and eye.
The present invention relates to novel beta-hairpin peptidomimetics of formula (I)
Wherein a single element T or P is linked in either direction from the carbonyl (C = O) attachment point to the nitrogen (N) of the next element, and wherein
T1And T2Independently are:
an L or D α -amino acid of one of the following formulae:
P1and P3Independently are:
-NR1CH(R19)CO-;
P2is-NR1C(R20)(R21) CO-; or-NR1C(Z)CO-;
P4is-NR1CH(R24)CO-;
A is O, NR9S, SO, or SO2
R1,R2And R3Independently is
H;CF3Lower alkyl, lower alkenyl, aryl-lower alkyl, or heteroaryl-lower alkyl;
R4,R5,R6,R7and R8Independently are:
H;F;CF3lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)13)oOR15;
-(CHR13)oSR15;-(CHR13)oNR15R16;-(CHR13)oOCONR15R16;
-(CHR13)oNR1CONR15R16;-(CHR13)oNR1COR15;-(CHR13)oCOOR15;
-(CHR13)oCONR15R16;-(CHR13)oPO(OR1)2;-(CHR13)oSO2R15;
-(CHR13)oNR1SO2R15;-(CHR13)oSO2NR15R16;-(CR1R13)oR30Or
-(CHR1)nO(CHR2)mR30Or
R4And R2Can be formed together
=O;-(CHR19)p-;-(CH2)nO(CH2)m-;-(CH2)nS(CH2)m-, or- (CH)2)nNR1(CH2)m-, or
R4And R5;R5And R6;R6And R7;R7And R8Or R6And R9Can be formed together
-(CHR19)p-;-(CH2)nO(CH2)m-;-(CH2)nS(CH2)m-, or- (CH)2)nNR1(CH2)m-;
R9And R10Independently are:
H;F;CF3lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)13)rOR15;
-(CHR13)rSR15;-(CHR10)rNR15R16;-(CHR13)rOCONR15R16;
-(CHR13)rNR1CONR15R16;-(CHR13)rNR1COR15;-(CHR13)oCOOR15;
-(CHR13)oCONR15R16;-(CHR13)rPO(OR1)2;-(CHR13)rSO2R15;
-(CHR13)rNR1SO2R15;-(CHR13)rSO2NR15R16;-(CR1R13)oR30Or
-(CHR1)rO(CHR1)oR30;
R11And R12Independently are:
H;F;Cl;Br;CF3;OCF3;OCHF2;CN;NO2lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)13)oOR15;
-(CHR13)oSR15;-(CHR13)oNR15R16;-(CHR13)oOCONR15R16;
-(CHR13)oNR1CONR15R16;-(CHR13)oNR1COR15;-(CHR13)oCOOR15;
-(CHR13)oCONR15R16;-(CHR13)oPO(OR1)2;-(CHR13)oSO2R15;
-(CHR13)oNR1SO2R15;-(CHR13)oSO2NR15R16Or (CR)1R13)oR30;
R13Is H, F, CF3Lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl;
cycloalkyl-lower alkyl, heterocycloalkyl-lower alkyl, aryl, heteroaryl;
aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)1)oOR15;-(CHR1)oSR15;
-(CHR1)oNR15R16;-(CHR1)oNC(=NR17)NR15R16;-(CHR1)oCOOR15;
-(CHR1)oCONR15R16;-(CHR1)oSO2R15Or (CHR)1)oSO2NR15R16;
R14Is H, CF3Lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl;
cycloalkyl-lower alkyl, heterocycloalkyl-lower alkyl, aryl, heteroaryl;
aryl-lower alkyl, heteroaryl-lower alkyl, cycloalkyl-aryl, heterocycloalkyl-aryl, cycloalkyl-heteroaryl, heterocycloalkyl-heteroaryl, aryl-cycloalkyl;
aryl-heterocycloalkyl, heteroaryl-cycloalkyl, heteroaryl-heterocycloalkyl;
-(CHR1)oOR15;-(CHR1)oSR15;-(CHR1)oNR15R16;-(CHR1)oCOOR15;
-(CHR1)oCONR15R16or (CHR)1)oSO2R15;
R15,R16,R17And R18Independently are:
h, lower alkyl, lower alkenyl, lower alkoxy, cycloalkyl, heterocycloalkyl;
cycloalkyl-lower alkyl, heterocycloalkyl-lower alkyl, aryl, heteroaryl;
aryl-lower alkyl, heteroaryl-lower alkyl, cycloalkyl-aryl, heterocycloalkyl-aryl, cycloalkyl-heteroaryl, heterocycloalkyl-heteroaryl, aryl-cycloalkyl;
aryl-heterocycloalkyl, heteroaryl-cycloalkyl, or heteroaryl-heterocycloalkyl, or
Structural element-NR15R16and-NR17R18Can be independently formed:
heterocycloalkyl, aryl-heterocycloalkyl, or heteroaryl-heterocycloalkyl;
or a group of one of the following formulae:
x and Y are independently:
-CR45or N;
R19is alkyl, alkenyl, cycloalkyl-lower alkyl, heterocycloalkyl-lower alkyl;
-(CR1R4)nR30;-(CH2)nO(CH2)mR30;-(CH2)nS(CH2)mR30or
-(CH2)nNR14(CH2)mR30;
R20And R21Independently are:
alkyl, alkenyl, - (CHR)4)oOR15;-(CHR4)oSR15Or (CHR)4)rNR15R16;
Z is- (CR)22R23)(n+m+1)-;-(CR22R23)nNR15(CR22R23)m-;-(CR22R23)nO(CR22R23)m-;
-(CR22R23)nS(CR22R23)m-;-O(CR22R23)rO-;
Or a group of one of the following formulae:
R22and R23Independently are:
H;F;CF3alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
aryl-lower alkyl or heteroaryl-lower alkyl; - (CR)1R13)oOR15;-(CR1R13)oSR15;
-(CR1R13)oNR15R16;-(CR1R13)oCOOR15;-(CR1R13)oCONR15R16Or
-(CR1R13)oSO2R15Or
R22And R23Can be formed together
=O;=NR1;=NOR1;=NOCF3;-(CHR1)p-, -O (CR)1R2)rO-;
R24Is alkyl, alkenyl;-(CR1R13)qNR15R16;-(CR1R13)qNR25R26;-(CR1R13)qNR14R27;
-(CH2)qC(=NR13)NR15R16;-(CH2)qC(=NOR17)NR15R16;
-(CH2)qC(=NNR15R16)NR17R18;-(CR1R13)qNR2C(=NR17)NR15R16;
-(CR1R13)qN=C(NR15R16)NR17R18;-(CR1R13)qOR14;-(CR1R13)qOR25;
-(CR1R13)qOR27;-(CR1R13)qSR15;-(CR1R13)qSO2R15;-(CR1R13)qNR14SO2R15;
-(CR1R13)qSO2NR1R14;-(CR1R13)qNR14SO2NR15R16;-(CR1R13)qSO2NR15R16;
-(CR1R13)qPO(OR1)2;-(CH2)nO(CH2)mNR15R16;
-(CH2)nO(CH2)mC(=NR17)NR15R16;
-(CH2)nO(CH2)mC(=NOR17)NR15R16;
-(CH2)nO(CH2)mC(=NNR15R16)NR17R18;
-(CH2)nO(CH2)mNR1C(=NR17)NR15R16;
-(CH2)nO(CH2)mN=C(NR15R16)NR17R18;-(CH2)nS(CH2)mNR15R16;
-(CH2)nS(CH2)mC(=NR17)NR15R16;
-(CH2)nS(CH2)mC(=NOR17)NR15R16;
-(CH2)nS(CH2)mC(=NNR15R16)NR17R18;
-(CH2)nS(CH2)mNR1C(=NR17)NR15R16;
-(CH2)nS(CH2)mN=C(NR15R16)NR17R18;-(CR1R13)qCOOR15;-(CR1R13)qCOOR25;
-(CR1R13)qCOOR28;-(CR1R13)qCONR15R16Or (CR)1R13)qCONR25R26;
Or, heteroaryl or heteroarylalkyl;
R25and R26Independently are:
H;-CH3;-[(CH2)2O]rCH3or- [ (CH)2)2O]rCF3;
R27is-COR19;-CO(CR1R13)oR15;-CO(CR1R13)oOR14;-CO(CR1R13)oNR15R16;
-CO(CR1R13)oNR2R14;-CO(CR1R19)NR15R16;-CO(CR1R29)NR15R16;
-CO(CHR1)oCONR15R16;-CO(CHR1)oCONR2SO2R15;-CO(CR1R13)oNR2SO2R15;
-CONR1(CHR15)nNR2(CHR13)mR14;-CO(CHR15)nO(CHR13)mR14;
-CONR1(CHR15)nO(CHR13)mR14;-SO2R19;-SO2(CR1R13)oR15;
-SO2(CR1R13)oNR15R16or-SO2(CR1R13)oNR1R25;
R28is-NR1C(R2)(R19)COOR15;-NR1C(R2)(R19)CONR15R16;-NR1C(R2)(R29)COOR15;
-NR1C(R2)(R29)CONR15R16;
R29Is- (CR)1R13)qNR15R16;-(CH2)qC(=NR17)NR15R16;-(CH2)qC(=NOR17)NR15R16;
-(CH2)qC(=NNR15R16)NR17R18;-(CR1R13)qNR2C(=NR16)NR14R15;
-(CR1R13)qN=C(NR15R16)NR17R18;-(CR1R13)qOR14;-(CR1R13)qSR15;
-(CR1R13)qSO2R15;-(CR1R13)qNR14SO2R15;-(CR1R13)qSO2NR1R14;
-(CR1R13)qSO2NR15R16;-(CR1R13)qNR2SO2NR15R16;
-(CR1R13)qPO(OR1)2;
-(CH2)nO(CH2)mNR15R16;-(CH2)nO(CH2)mC(=NR17)NR15R16;
-(CH2)nO(CH2)mC(=NOR17)NR15R16;
-(CH2)nO(CH2)mC(=NNR15R16)NR17R18;
-(CH2)nO(CH2)mNR14C(=NR17)NR15R16;
-(CH2)nO(CH2)mN=C(NR15R16)NR17R18;
-(CH2)nS(CH2)mNR15R16;-(CH2)nS(CH2)mNR15R16;
-(CH2)nS(CH2)mC(=NR17)NR15R16;
-(CH2)nS(CH2)mC(=NOR17)NR15R16;
-(CH2)nS(CH2)mC(=NNR15R16)NR17R18;
-(CH2)nS(CH2)mNR14C(=NR17)NR15R16;
-(CH2)nS(CH2)mN=C(NR15R16)NR17R18;-(CR1R13)qCOOR15Or
-(CR1R13)qCONR15R16;
R30An aryl group of one of the following formulae
Or a heteroaryl group of one of the formulae
R31And R32Independently are:
H;F;Cl;Br;NO2;CN;CF3;OCHF2;OCF3lower alkyl, lower alkenyl;
aryl-lower alkyl, aryl, heteroaryl, - (CH)2)oR33;-(CH2)oOR15;-O(CH2)oR33;
-(CH2)oSR15;-(CH2)oNR15R16;-(CH2)oOCONR15R16;-(CH2)oNR1CONR15R16;
-(CH2)oNR1COR15;-(CH2)oCOOR15;-(CH2)oCONR15R16;-(CH2)oPO(OR1)2;
-(CH2)oSO2R14Or (CH)2)oCOR15;
R33Is an aryl radical of the formula
R34,R35And R36Independently are:
H;F;Cl;Br;OH;NH2;NO2;CN;CF3;OCHF2;OCF3;-NR1R15;-(CH2)oCOOR15;
-(CH2)oCONR1R15lower alkyl, lower alkoxy, or lower alkenyl;
R37is H, lower alkyl, or aryl-lower alkyl;
R38,R39,R40and R41Independently are:
H;F;CF3lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)1)oOR15;
-(CHR1)oSR15;-(CHR1)oNR2R15;-(CHR1)oOCONR2R15;-(CHR1)oNR2CONR3R15;-(CHR1)oNR2COR15;-(CHR1)oCOOR15;-(CHR1)oCONR2R15;
-(CHR1)oPO(OR2)2;-(CHR1)oSO2R15;-(CHR1)oNR2SO2R15;-(CHR1)oSO2NR2R15;-(CR1R2)oR33Or (CHR)1)nO(CHR2)mR33;
R42And R43Independently are:
H;F;CF3lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)1)rOR15;-(CHR1)rSR15;-(CHR1)rNR2R15;-(CHR1)rOCONR2R15;-(CHR1)rNR2C ONR3R15;
-(CHR1)rNR2COR15;-(CHR1)oCOOR15;-(CHR1)oCONR2R15;-(CHR1)rPO(OR2)2;-(CHR1)rSO2R15;-(CHR1)rNR2SO2R15;-(CHR1)rSO2NR2R15;-(CR1R2)oR33Or
-(CHR1)rO(CHR2)oR33;
R44And R45Independently are:
H;F;Cl;Br;CF3;OCF3;OCHF2;CN;NO2lower alkyl, lower alkenyl, aryl, heteroaryl, aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)1)oOR15;
-(CHR1)oSR15;-(CHR1)oNR2R15;-(CHR1)oOCONR2R15;-(CHR1)oNR2CONR3R15;
-(CHR1)oNR2COR15;-(CHR1)oCOOR15;-(CHR1)oCONR2R15;-(CHR1)oPO(OR2)2;
-(CHR1)oSO2R15;-(CHR1)oNR2SO2R15;-(CHR1)oSO2NR2R15Or (CR)1R2)oR33;
n and m are independently integers from 0 to 5, provided that n + m.ltoreq.6;
o is 0-4, p is 2-6, q is 1-6, r is 1-3;
or a pharmaceutically acceptable salt thereof.
In a particular formula, each single radical "R" having the same index x (x = -45)x"independently selected, and thus, they are the same or different.
The term "alkyl", as used in this specification, alone or in combination with (i.e. as part of) another group, e.g. arylalkyl, represents a saturated, straight-chain or branched, optionally substituted hydrocarbon group having up to 12, preferably up to 8, carbon atoms. According to a preferred embodiment of the invention, "alkyl" is "lower alkyl", which stands for an alkyl group having up to 6 carbon atoms.
The term "alkenyl", alone or in combination with another group, represents a straight-chain or branched hydrocarbon radical having up to 12, preferably up to 8, carbon atoms and comprising at least one or up to 4 (depending on the length of the chain) olefinic double bonds. Such alkenyl moieties are optionally substituted and may exist in the E or Z configuration, both of which are part of the present invention.
The term "cycloalkyl", alone or in combination, refers to a saturated or partially unsaturated cycloaliphatic moiety having from 3 to 10 carbon atoms and which is optionally substituted. Examples of such moieties include, but are not limited to: cyclohexyl, norbonyl, decalinyl, and the like.
The term "heterocycloalkyl", alone or in combination, describes a saturated or partially unsaturated mono-or bicyclic moiety having from 3 to 9 ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen or sulfur. The term includes, for example: morpholine, piperazine, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl, 1, 7-diazaspiro [4.4] nonane, and the like. The heterocycloalkyl ring may be optionally substituted.
The term "aryl", alone or in combination, represents an aromatic carbocyclic hydrocarbon radical containing 1 or 2 six-membered rings, such as phenyl or naphthyl, which may be substituted by up to 3 substituents such as Br, Cl, F, CF3,OCF3,OCHF2,N(CH3)2,NO2Lower alkyl, lower alkenyl, phenyl or phenoxy optionally substituted.
The term "heteroaryl", alone or in combination, represents an aromatic heterocyclic group containing 1 or 2 5-and/or 6-membered rings, at least one of which contains up to 3 heteroatoms selected from O, S and N, and wherein heteroaryl or its tautomeric form may be attached via any suitable atom. The heteroaryl ring may be optionally substituted, for example, with substituents as described above for aryl.
The term "arylalkyl", as used herein, refers to: an alkyl group as defined above substituted with an aryl group as defined above. Examples of arylalkyl moieties include, but are not limited to: benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and the like. Similarly, the term "aryl-lower alkyl" refers to the moieties described above, but wherein the alkyl is "lower alkyl".
The term "heteroarylalkyl" as used herein refers to: an alkyl group as defined above substituted with a heteroaryl group as defined above. Similarly, the term "heteroaryl-lower alkyl" refers to the moieties described above, but wherein the alkyl is "lower alkyl".
The term "aryl-cycloalkyl" as used herein refers to: cycloalkyl as defined above substituted or annelated with aryl as defined above. Examples of aryl-cycloalkyl moieties include, but are not limited to: phenylcyclopentyl, 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, and the like.
The term "aryl-heterocycloalkyl" as used herein refers to: a heterocycloalkyl group as defined above substituted or annelated with an aryl group as defined above. Examples of aryl-heterocycloalkyl moieties include, but are not limited to: indolinyl, 1,2,3, 4-tetrahydroquinolinyl, and the like.
The term "heteroaryl-cycloalkyl" as used herein refers to: cycloalkyl as defined above substituted or annelated with heteroaryl as defined above. Examples of heteroaryl-cycloalkyl moieties include, but are not limited to: 5,6,7, 8-tetrahydroquinolyl and the like.
The term "heteroaryl-heterocycloalkyl" as used herein refers to: heterocycloalkyl as defined above substituted or annelated with heteroaryl as defined above. Examples of heteroaryl-heterocycloalkyl moieties include, but are not limited to: 4- (thiazol-2-yl) piperazinyl, 5,6,7, 8-tetrahydro-1, 6-naphthyridinyl, and the like.
The terms "cycloalkyl-aryl", "heterocycloalkyl-aryl", "cycloalkyl-heteroaryl" and "heterocycloalkyl-heteroaryl" as used herein are similarly defined according to the terms "aryl-cycloalkyl", "aryl-heterocycloalkyl", "heteroaryl-cycloalkyl" and "heteroaryl-heterocycloalkyl" as defined above, but are attached in the opposite orientation, e.g., as opposed to 4- (thiazol-2-yl) piperazinyl, which term refers to 2- (piperazin-1-yl) thiazolyl and the like.
The terms "alkoxy" and "aryloxy", alone or in combination, refer to-O-alkyl and-O-aryl, respectively, wherein alkyl or aryl is as defined above.
The term "optionally substituted" means: one group, such as but not limited to alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxy, and aryloxy, may be substituted with one or more substituents independently selected from the group consisting of, but not limited to: amino (-NH)2) Dimethylamino group, nitro group (-NO)2) Halogen (F, Cl, Br, I), CF3Cyano (-CN), hydroxyl, methoxy, oxygen (= O), carboxyl, phenyl, phenoxy, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, and the like.
The term "lower" represents radicals and compounds having up to 6 atoms. Thus, for example, the term "lower alkyl" represents a saturated, straight-chain or branched hydrocarbon group having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like, and may be optionally substituted.
The peptidomimetics of the invention may also be diastereomers (e.g., epimers) or enantiomers of the compounds of formula (I). These stereoisomers may be prepared by modifications of the methods described below, using either the epimers or enantiomers of the chiral starting material. In the above description, each single epimer as well as mixtures of both are part of the invention, with undefined stereoisomeric chemistry.
Another embodiment of the present invention may also include compounds that: which is identical to the compound of formula (I) except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. enriched in2H(D)、3H、11C、14C、127I, etc. These isotopic analogs, and pharmaceutical salts and formulations thereof, are considered therapeutically and/or diagnostically useful agents, for example, but not limited to, wherein fine adjustment of the half-life in vivo can result in an optimized dosage regimen.
Particular embodiments of the present invention relate to derivatives of formula (I) wherein, in particular,
T1is thatDPro;DPip, orDAze;
T2Is an L or D α -amino acid of one of the following formulae:
R14is H, CF3Lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl;
cycloalkyl-lower alkyl, heterocycloalkyl-lower alkyl, aryl, heteroaryl;
aryl-lower alkyl, heteroaryl-lower alkyl; - (CHR)1)sOR15;-(CHR1)sSR15;
-(CHR1)sNR15R16;-(CHR1)oCOOR15;-(CHR1)oCONR15R16Or (CHR)1)oSO2R15;
R15,R16,R17And R18Independently are:
h, lower alkyl, lower alkenyl, lower alkoxy, cycloalkyl, heterocycloalkyl;
cycloalkyl-lower alkyl, heterocycloalkyl-lower alkyl, aryl, heteroaryl;
aryl-lower alkyl, or heteroaryl-lower alkyl, or
Structural element-NR15R16and-NR17R18Groups of one of the following formulae may be formed independently:
R24is alkyl, alkenyl; - (CR)1R13)qNR15R16;-(CR1R13)qNR25R26;-(CR1R13)qNR14R27;
-(CH2)qC(=NR17)NR15R16;-(CR1R13)qNR2C(=NR17)NR15R16;
-(CR1R13)qOR15;
-(CR1R13)qOR25;-(CR1R13)qOR27;-(CR1R13)qSR15;
-(CR1R13)qSO2R15;
-(CR1R13)qNR15SO2R16;-(CR1R13)qSO2NR1R14;
-(CR1R13)qSO2NR15R16;
-(CH2)nO(CH2)mNR15R16;-(CH2)nO(CH2)mC(=NR17)NR15R16;
-(CH2)nO(CH2)mNR1C(=NR17)NR15R16;
-(CH2)nO(CH2)mN=C(NR15R16)NR17R18;
-(CH2)nS(CH2)mNR15R16;-(CR1R13)qCOOR15;-(CR1R13)qCOOR25;
-(CR1R13)qCOOR28;-(CR1R13)qCONR15R16Or
-(CR1R13)qCONR25R26;
Or heteroaryl, or heteroarylalkyl;
s is 2 to 4;
wherein all other elements of formula (I) are as defined above.
In another embodiment of the invention, the element of formula (I) is as defined below:
T1is thatDPro;DPip, orDAze;
T2Is an L or D α -amino acid of one of the following formulae:
P1and P3Independently are:
His;His(Me);His(Bn);hHis;Phe;Phe(2Cl);Phe(3Cl);Phe(4Cl);Phe(3,4Cl2);Phe(2F);Phe(3F);Phe(4F);Phe(3,4F2);Phe(3CN);Phe(4CN);Phe(2CF3);Phe(3CF3);Phe(4CF3);Phe(3,4(CF3)2);Phe(4COOMe);hPhe;Thi;Tza;Trp;Trp(5OH);Trp(5Cl);Trp(6Cl);Trp(5,6Cl2);Trp(5Br);Trp(6Br);Trp(6CF3) Trp (7Aza), hTerp, Tyr, (Tyr) (Me), Tyr (Ph), Tyr (Bn), Tyr (4OHPh), Tyr (4MeOCOBn), hTyr, Thr (Bn), Ser (Bn), 2Pal, 3Pal, 4Pal, Phg, Ala (2 furyl), Ala (3 furyl), Ala (2Quin), Ala (3Quin), Ala (4Quin), Ala (tBu), Gly (tBu), 1Nal, 2Nal, Nle (6OBn), Cha, hCha, Bip, Bbta, or OctG;
P2is Aib, Ac3c, Ac4c, Cyp, Chx (4oxo), Ac7c, Ac8c;DAtc;LAtc;DLatc, Deg, or 4,4-AC-ThiothP;
P4is Arg, hArg, (Ala) (Ppz), Thr, alloThr, Gln, (Gln) (Me)2);Gln(iPr);Gln(cPr);Gln(iBu);Glu(Ala);Glu(DAla);Glu(Arg);Glu(DArg);Glu(Glu);Glu(Gly);Glu(His);Glu(Leu);Glu(DLeu);Glu(2Nal);Glu(Sar);Glu(Trp);Glu(DTrp);Cys;hCys;Ser;hSer;Ser(Me);hSer(Me);Thr;Met;Met(O2);Lys;hLys;Lys(Ac);Lys(Me);Lys(Bz);Lys(Nic);Lys(4Oxa);Lys((5R)OH);Orn;Dap;Dap(MeO(CH2)2);Dap(CONH2);Dap((MeO(CH2)2)2);Dab(Sar);Dab;Dab(Ac);Dab(Ala);Dab(DAla);Dab(Arg);Dab(DArg);Dab(Dab);Dab(Glu);Dab(Gly);Dab(His);Dab(Leu);Dab(DLeu);Dab(MEMCO);Dab(4Me2NPhSO2);Dab(MeO(CH2)2NHCO);Dab((MeO(CH2)2)(Me)NCO);Dab(MePpzCO);Dab(MeSO2);Dab(morphCO);Dab(2Nal);Dab(Trp);Dab(DTrp);Dab(Sar);Gln(Alk1);Gln(Alk2);Gln(Alk3);Gln(Alk4);Gln(Alk5);Gln(Alk6);Gln(Alk7);Gln(Alk8);Gln(Alk9);Gln(Alk10);Gln(Alk11);Gln(Alk12);Gln(Alk13);Gln(Alk14);Gln(Alk15);Gln(Alk16);Gln(Alk17);Gln(Alk18);Gln(Alk19);Gln(Alk20);Gln(Alk21);Gln(Alk22);Gln(Alk23);Gln(Alk24);Gln(Alk25);Gln(Alk26);Gln(Alk27);Gln(Alk28);Gln(Alk29);Gln(Alk30);Gln(Alk31);Gln(Alk32);Gln(Alk33);Gln(Alk34);Glu(cN1);Glu(cN2);Glu(cN3);Glu(cN4);Glu(cN5);Glu(cN6);Glu(cN7);Glu(cN8);Glu(cN9);Glu(cN10);Glu(cN11);Glu(cN12);Glu(cN13);Glu(cN14);Glu(cN15);Glu(cN16);Glu(cN17);Sab(N1);Sab(N2);Sab(N3);Sab(N4);Sab(N5);Sab(N6);Sab(N7);Sab(N8);Sab(N9);Sab(N10);Sab(N11);Sab(N12);Sab(N13);Sab(N14);Sab(N15);Sab(N16);Sab(N17);Sab(N18);Sab(N19);Sab(N20);Sab(N21);Sab(N22);Sab(N23);Sab(N24);Sab(N25);Sab(N26);Sab(N27);Sab(N28);Sab(N29);Sab(N30);Sab(N31);Sab(N32);Sab(N33);Sab(N34);Sab(N35);Sab(N36);Sab(N37);Sab(N38);Sab(N39);Sab(N40);Sab(N41);Sab(N42);Sab(N43);Sab(N44);Sab(N45);Sab(N46);Sab(N47);Sab(N48);Sab(N49);Sab(N50);Sab(N51);Sab(N52);Sab(N53);Sab(N54);Sab(N55);Sab(N56);Sab(N57);Sab(N58);Sab(N59);Sab(N60);Sab(N61);Dab(SN1);Dab(SN2);Dab(SN3);Dab(SN4);Dab(SN5);Dab(SN6);Dab(SN7);Dab(SN8);Dab(SN9);Dab(SN10);Dab(SN11);Dab(SN12);Dab(SN13);Dab(SN14);Dab(SN15);Dab(SN16);Dab(SN17);Dab(SN18);Dab(SN19);Dab(SN20);Dab(SN21);Dab(SN22);Dab(SN23);Dab(SN24);Dab(SN25);Dab(SN26);Dab(SN27);Dab(SN28);Dab(SN29);Dab(SN30);Dab(SN31);Dab(SN32);Dab(SN33);Dab(SN34);Dab(SN35);Dab(SN36);Dab(SN37);Dab(SN38);Dab(SN39);Dab(SN40);Dab(SN41);Dab(SN42);Dab(SN43);Dab(SN44);Dab(SN45);Dab(SN46);Dab(SN47);Dab(SN48);Dab(SN49);Dab(SN50);Dab(SN51);Dab(SN52);Dab(SN53);Dab(SN54);Dab(SN55);Dab(SN56);Dab(SN57);Dab(SN58);Dab(SN59);Dab(SN60);Dab(SN61);Dab(UN1);Dab(UN2);Dab(UN3);Dab(UN4);Dab(UN5);Dab(UN6);Dab(UN7);Dab(UN8);Dab(UN9);Dab(UN10);Dab(UN11);Dab(UN12);Dab(UN13);Dab(UN14);Dab(UN15);Dab(UN16);Dab(UN17);Dab(UN18);Dab(UN19);Dab(UN20);Dab(UN21);Dab(UN22);Dab(UN23);Dab(UN24);Dab(UN25);Dab(UN26);Dab(UN27);Dab(UN28);Dab(UN29);Dab(UN30);Dab(UN31);Dab(UN32);Dab(UN33);Dab(UN34);Dab(UN35);Dab(UN36);Dab(UN37);Dab(UN38);Dab(UN39);Dab(UN40);Dab(UN41);Dab(UN42);Dab(UN43);Dab(UN44);Dab(UN45);Dab(UN46);Dab(UN47);Dab(UN48);Dab(UN49);Dab(UN50);Dab(UN51);Dab(UN52);Dab(UN53);Dab(UN54);Dab(UN55);Dab(UN56);Dab(UN57);Dab(UN58);Dab(UN59);Dab(UN60);Dab(UN61);Dab(S1);Dab(S2);Dab(S3);Dab(S4);Dab(S5);Dab(S6);Dab(S7);Dab(S8);Dab(S9);Dab(S10);Dab(S11);Dab(S12);Dab(S13);Dab(S14);Dab(S15);Dab(S16);Dab(S17);Dab(S18);Dab(A1);Dab(A2);Dab(A3);Dab(A4);Dab(A5);Dab(A6);Dab(A7);Dab(A8);Dab(A9);Dab(A10);Dab(A11);Dab(A12);Dab(A13);Dab(A14);Dab(A15);Dab(A16);Dab(A17);Dab(A18);Dab(A19);Dab(A20);Dab(A21);Dab(A22);Dab(A23);Dab(A24);Dab(A25);Dab(A26);Dab(A27);Dab(A28);Dab(A29);Dab(A30);Dab(A31);Dab(A32);Dab(A33);Dab(A34);Dab(A35);Dab(A36);Dab(A37);Dab(A38);Dab(A39);Dab(A40);Dab(A41);Dab(A42);Dab(A43);Dab(A44);Dab(A45);Dab(A46);Dab(A47);Dab(A48);Dab(A49);Dab(A50);Dab(A51);Dab(A52);Dab(A53);Dab(A54);Dab(A55);Dab(A56);Dab(Suc1);Dab(Suc2);Dab(Suc3);Dab(Suc4);Dab(Suc5);Dab(Suc6);Dab(Suc7);Dab(Suc8);Dab(Suc9);Dab(Suc10);Asn(Alk1);Asn(Alk2);Asn(Alk3);Asn(Alk4);Asn(Alk5);Asn(Alk6);Asn(Alk7);Asn(Alk8);Asn(Alk9);Asn(Alk10);Asn(Alk11);Asn(Alk12);Asn(Alk13);Asn(Alk14);Asn(Alk15);Asn(Alk16);Asn(Alk17);Asn(Alk18);Asn(Alk19);Asn(Alk20);Asn(Alk21);Asn(Alk22);Asn(Alk23);Asn(Alk24);Asn(Alk25);Asn(Alk26);Asn(Alk27);Asn(Alk28);Asn(Alk29);Asn(Alk30);Asn(Alk31);Asn(Alk32);Asn(Alk33);Asn(Alk34);Asp(cN1);Asp(cN2);Asp(cN3);Asp(cN4);Asp(cN5);Asp(cN6);Asp(cN7);Asp(cN8);Asp(cN9);Asp(cN10);Asp(cN11);Asp(cN12);Asp(cN13);Asp(cN14);Asp(cN15);Asp(cN16);Asp(cN17);Sap(N1);Sap(N2);Sap(N3);Sap(N4);Sap(N5);Sap(N6);Sap(N7);Sap(N8);Sap(N9);Sap(N10);Sap(N11);Sap(N12);Sap(N13);Sap(N14);Sap(N15);Sap(N16);Sap(N17);Sap(N18);Sap(N19);Sap(N20);Sap(N21);Sap(N22);Sap(N23);Sap(N24);Sap(N25);Sap(N26);Sap(N27);Sap(N28);Sap(N29);Sap(N30);Sap(N31);Sap(N32);Sap(N33);Sap(N34);Sap(N35);Sap(N36);Sap(N37);Sap(N38);Sap(N39);Sap(N40);Sap(N41);Sap(N42);Sap(N43);Sap(N44);Sap(N45);Sap(N46);Sap(N47);Sap(N48);Sap(N49);Sap(N50);Sap(N51);Sap(N52);Sap(N53);Sap(N54);Sap(N55);Sap(N56);Sap(N57);Sap(N58);Sap(N59);Sap(N60);Sap(N61);Dap(SN1);Dap(SN2);Dap(SN3);Dap(SN4);Dap(SN5);Dap(SN6);Dap(SN7);Dap(SN8);Dap(SN9);Dap(SN10);Dap(SN11);Dap(SN12);Dap(SN13);Dap(SN14);Dap(SN15);Dap(SN16);Dap(SN17);Dap(SN18);Dap(SN19);Dap(SN20);Dap(SN21);Dap(SN22);Dap(SN23);Dap(SN24);Dap(SN25);Dap(SN26);Dap(SN27);Dap(SN28);Dap(SN29);Dap(SN30);Dap(SN31);Dap(SN32);Dap(SN33);Dap(SN34);Dap(SN35);Dap(SN36);Dap(SN37);Dap(SN38);Dap(SN39);Dap(SN40);Dap(SN41);Dap(SN42);Dap(SN43);Dap(SN44);Dap(SN45);Dap(SN46);Dap(SN47);Dap(SN48);Dap(SN49);Dap(SN50);Dap(SN51);Dap(SN52);Dap(SN53);Dap(SN54);Dap(SN55);Dap(SN56);Dap(SN57);Dap(SN58);Dap(SN59);Dap(SN60);Dap(SN61);Dap(UN1);Dap(UN2);Dap(UN3);Dap(UN4);Dap(UN5);Dap(UN6);Dap(UN7);Dap(UN8);Dap(UN9);Dap(UN10);Dap(UN11);Dap(UN12);Dap(UN13);Dap(UN14);Dap(UN15);Dap(UN16);Dap(UN17);Dap(UN18);Dap(UN19);Dap(UN20);Dap(UN21);Dap(UN22);Dap(UN23);Dap(UN24);Dap(UN25);Dap(UN26);Dap(UN27);Dap(UN28);Dap(UN29);Dap(UN30);Dap(UN31);Dap(UN32);Dap(UN33);Dap(UN34);Dap(UN35);Dap(UN36);Dap(UN37);Dap(UN38);Dap(UN39);Dap(UN40) Dap (UN), Dap (S), Dap (A), Dap (A), Dap (A), Dap (A), and a Dap (A), a A19) Dap (A20), Dap (A21), Dap (A22), Dap (A23), Dap (A24), Dap (A25), Dap (A26), Dap (A27), Dap (A28), Dap (A29), Dap (29), Dap (A29), Dap (29), Dap (A29), Dap (Su3672), Dap 29), Dap (Su3672, Dap 29, Da;
or His, His (Me), His (Bn), hHis, Lat, Trp (5OH), Trp (5Cl), Trp (6Cl), Trp (5,6Cl)2);Trp(5Br);Trp(6Br);Trp(6CF3) Trp (7Aza), hTRp, Tza, 2Pal, 3Pal, 4Pal, h2Pal, h3Pal, h4Pal, Ala (1Im), Ala (2Im), hAla (1Im), hAla (2Im), Ala (pyrazinyl), Ala (1 pyrazolyl), Ala (3 pyrazolyl), Ala (2 pyrimidine), Ala (4 pyrimidine), Ala (5 pyrimidine), Ala (2Quin), Ala (3Quin), or Ala (4Quin);
or a pharmaceutically acceptable salt thereof.
In another embodiment of the invention, the element of formula (I) is as defined below:
T1is thatDPro;DPip, orDAze;
T2Is an L or D α -amino acid of one of the following formulae:
P1and P3Independently are:
His;His(Me);His(Bn);hHis;Phe;Phe(2Cl);Phe(3Cl);Phe(4Cl);Phe(3,4Cl2);Phe(2F);Phe(3F);Phe(4F);Phe(3,4F2);Phe(3CN);Phe(4CN);Phe(2CF3);Phe(3CF3);Phe(4CF3);Phe(3,4(CF3)2);Phe(4COOMe);hPhe;Thi;Tza;Trp;Trp(5OH);Trp(5Cl);Trp(6Cl);Trp(5,6Cl2);Trp(5Br);Trp(6Br);Trp(6CF3) Trp (7Aza), hTerp, Tyr, (Tyr) (Me), Tyr (Ph), Tyr (Bn), Tyr (4OHPh), Tyr (4MeOCOBn), hTyr, Thr (Bn), Ser (Bn), 2Pal, 3Pal, 4Pal, Phg, Ala (2 furyl), Ala (3 furyl), Ala (2Quin), Ala (3Quin), Ala (4Quin), Ala (tBu), Gly (tBu), 1Nal, 2Nal, Nle (6OBn), Cha, hCha, Bip, Bbta, or OctG;
P2is Aib, Ac3c, Ac4c, Cyp, Chx (4oxo), Ac7c, Ac8c;DAtc;LAtc;DLatc, Deg, or 4,4-AC-ThiothP;
P4is Arg, hArg, (Ala) (Ppz), Thr, alloThr, Gln, (Gln) (Me)2);Gln(iPr);Gln(cPr);Gln(iBu);Glu(Ala);Glu(DAla);Glu(Arg);Glu(DArg);Glu(Glu);Glu(Gly);Glu(His);Glu(Leu);Glu(DLeu);Glu(2Nal);Glu(Sar);Glu(Trp);Glu(DTrp);Cys;hCys;Ser;hSer;Ser(Me);hSer(Me);Thr;Met;Met(O2);Lys;hLys;Lys(Ac);Lys(Me);Lys(Bz);Lys(Nic);Lys(4Oxa);Lys((5R)OH);Orn;Dap;Dap(MeO(CH2)2);Dap(CONH2);Dap((MeO(CH2)2)2);Dab(Sar);Dab;Dab(Ac);Dab(Ala);Dab(DAla);Dab(Arg);Dab(DArg);Dab(Dab);Dab(Glu);Dab(Gly);Dab(His);Dab(Leu);Dab(DLeu);Dab(MEMCO);Dab(4Me2NPhSO2);Dab(MeO(CH2)2NHCO);Dab((MeO(CH2)2)(Me)NCO);Dab(MePpzCO);Dab(MeSO2);Dab(morphCO);Dab(2Nal);Dab(Trp);Dab(DTrp), Dab (Sar), or Dab (SN13);
or His, His (Me), hHis, 2Pal, 3Pal, 4Pal, h2Pal, h3Pal, h4Pal, Trp, Ala (1Im), Ala (2Im), hAla (1Im), hAla (2Im), or Ala (2 pyrimidine);
or a pharmaceutically acceptable salt thereof.
In another embodiment of the invention, the element of formula (I) is as defined below:
T1is thatDPro;DPip, orDAze;
T2Is Pro;DPro;Oic;Pip;Tic;Tic(7OH);Thz;Thz(5,5Me2);Pro((4S)F);Pro(5,5Me2) Pro ((4S) cHex); Pro ((4R) Ph); Pro ((4R) Bn); Pro ((4R)4BrBn); Pro ((4R)3CNBn); Hyp (Ph); Hyp (Bn); Hyp (4BrBn); Hyp (3CNBn); Hyp (4CNBn); Hyp (CONHPh); or (4S) -Hyp (Bn); and;
P1and P3Independently are:
Phe;Phe(4Cl);Phe(4F);Phe(4CN);Phe(3CF3);Phe(4CF3);Phe(4COOMe);Trp;
trp (5OH), Trp (6Cl), Tyr, (Tyr (Me) Tyr (Ph)), Tyr (4OHPh), Tyr (4MeOCOBn), hTyr, Ala (2 furyl), Ala (2Quin), 2Nal, Nle (6OBn);DLtrp (7Aza), Cha, Bip, Bbta, or octG;
P2is Aib, Ac3c, Ac4c, Cyp, Chx (4oxo), Ac7c, Ac8c;DLatc, Deg, or 4,4-AC-ThiothP;
P4is Arg, hArg, (Ala), (Ppz), Thr, alloThr, Gln, (Gln), (iPr), Gln (cPr), Glu (Ala), Glu (Glu), (PpZ)DAla);Glu(Arg);Glu(DArg);Glu(Glu);Glu(Gly);Glu(His);Glu(Leu);Glu(DLeu);Glu(2Nal);Glu(Sar);Glu(Trp);Glu(DTrp);Cys;hCys;Ser;hSer;Ser(Me);hSer(Me);Thr;Met;Met(O2);Lys;hLys;Lys(Ac);Lys(Me);Lys(Bz);Lys(Nic);Lys(4Oxa);Lys((5R)OH);Dap;Dap(MeO(CH2)2);Dap(CONH2);Dap((MeO(CH2)2)2);Dab;Dab(Ac);Dab(morphCO);Dab(MePpzCO);Dab(MEMCO);Dab(MeO(CH2)2NHCO);Dab((MeO(CH2)2)(Me)NCO);Dab(MeSO2);Dab(4Me2NPhSO2) Dab (Dab); or Dab (SN13);
or His, hHis, 2Pal, 3Pal, or 4Pal;
or a pharmaceutically acceptable salt thereof.
The following is a list of abbreviations corresponding to the commonly employed practice of the amino acids or residues thereof mentioned herein for ethyl suitable for the purposes of the present invention.
Although amino acids are specifically described, it will be apparent to those skilled in the art that derivatives of these amino acids having similar structural and physicochemical properties produce functional analogs having similar biological activities and thus form part of the spirit of the present invention.
Ala L-alanine
Arg L-arginine
Asn L-asparagine
Asp L-aspartic acid
Cit L-citrulline
Cys L-cysteine
Glu L-glutamic acid
Gln L-Glutamine
Gly glycine
His L-histidine
Ile L-isoleucine
Leu L-leucine
Lys L-lysine
Met L-methionine
Orn L-Ornithine
Phe L-phenylalanine
Pro L-proline
Ser L-serine
Thr L-threonine
Trp L-Tryptophan
Tyr L-tyrosine
Val L-valine
Ac3c 1-Aminocyclopropanecarboxylic acid
Ac4c 1-Aminocyclobutanecarboxylic acid
Ac7c 1-amino cycloheptanecarboxylic acid
Ac8c 1-aminocyclooctane carboxylic acid
Ala (tBu) (S) -2-amino-4, 4-dimethylpentanoic acid
Ala (2 furyl) (S) -2-amino-3- (furan-2-yl) propionic acid
Ala (3 furyl) (S) -2-amino-3- (furan-3-yl) propionic acid
Ala (1Im) (S) -2-amino-3- (1H-imidazol-1-yl) propionic acid
Ala (2Im) (S) -2-amino-3- (1H-imidazol-2-yl) propionic acid
Ala (Ppz) (S) -2-amino-3- (piperazin-1-yl) propionic acid
Ala (pyrazinyl) (S) -2-amino-3- (pyrazin-2-yl) propionic acid
Ala (1 pyrazolyl) (S) -2-amino-3- (1H-pyrazol-1-yl) propionic acid
Ala (3 pyrazolyl) (S) -2-amino-3- (1H-pyrazol-3-yl) propionic acid
Ala (2-pyrimidine) (S) -2-amino-3- (pyrimidin-2-yl) propionic acid
Ala (4-pyrimidine) (S) -2-amino-3- (pyrimidin-4-yl) propionic acid
Ala (5-pyrimidine) (S) -2-amino-3- (pyrimidin-5-yl) propionic acid
Ala (2Quin) (S) -2-amino-3- (quinolin-2-yl) propionic acid
Ala (3Quin) (S) -2-amino-3- (quinolin-3-yl) propionic acid
Ala (4Quin) (S) -2-amino-3- (quinolin-4-yl) propionic acid
Aib 2-methyl-2-aminopropionic acid
DLAtc (R, S) -2-amino-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid
Aze (S) -azetidine-2-carboxylic acid
4, 4-AC-Thioph 4-aminotetrahydro-2H-thiopyran-4-carboxylic acid
Bbta (S) -2-amino-3- (1-benzothien-3-yl) propionic acid
Bip (S) -2-amino-3- (4-biphenylyl) propionic acid
Cha (S) -2-amino-3-cyclohexylpropionic acid
Chx 1-aminocyclohexanecarboxylic acid
Chx (4oxo) 1-amino-4-oxo-cyclohexanecarboxylic acids
Cyp 1-aminocyclopentanecarboxylic acids
Dab (S) -2, 4-diaminobutyric acid
Dab (Ac) (S) -4-acetylamino-2-aminobutyric acid
Dab (Ala) (S) -2-amino-4- ((S) -2-aminopropionamide) butyric acid
Dab(DAla) (S) -2-amino-4- ((R) -2-aminopropionamide) butyric acid
Dab (Arg) (S) -2-amino-4- ((S) -2-amino-5-guanidinopentanamide) butanoic acid
Dab(DArg) (S) -2-amino-4- ((R) -2-amino-5-guanidinopentanamide) butanoic acid
Dab (dab) (S) -2-amino-4- ((S) -2, 4-diaminobutanamide) butanoic acid
Dab (Glu) (S) -4-amino-5- ((S) -3-amino-3-carboxypropylamino) -5-oxopentanoic acid
Dab (Gly) -2-amino-4- (2-aminoacetamido) butanoic acid
Dab (His) (S) -2-amino-4- ((S) -2-amino-3- (1H-imidazol-5-yl) -propionamide) butyric acid
Dab (Leu) (S) -2-amino-4- ((S) -2-amino-4-methylpentanamide) butanoic acid
Dab(DLeu) (S) -2-amino-4- ((R) -2-amino-4-methylpentanamide) butanoic acid
Dab (MEMCO) (S) -2-amino-4- (2- (2-methoxyethoxy) acetylamino) butanoic acid
Dab(4Me2NPhSO2) (S) -2-amino-4- (4- (dimethylamino) phenylsulphonamido) butanoic acid
Dab(MeO(CH2)2NHCO) (S) -2-amino-4- (3- (2-methoxyethyl) ureido) butanoic acid
Dab((MeO(CH2)2) (Me) NCO) (S) -2-amino-4- (3- (2-methoxyethyl) -3-methylureido) -butyric acid
Dab (MePpZCO) (S) -2-amino-4- (4-methylpiperazine-1-carboxyamino) butanoic acid
Dab(MeSO2) (S) -2-amino-4- (methylsulphonamido) butanoic acid
Dab (morphco) (S) -2-amino-4- (morpholine-4-carboxyamino) butanoic acid
Dab (2Nal) (S) -2-amino-4- ((S) -2-amino-3- (naphthalen-2-yl) -propionamide) butanoic acid
Dab (Trp) (S) -2-amino-4- ((S) -2-amino-3- (1H-indol-3-yl) propanamide) -butyric acid
Dab (DTrp) (S) -2-amino-4- ((R) -2-amino-3- (1H-indol-3-yl) propionamide) -butyric acid
Dab (Sar) (S) -2-amino-4- (2- (methylamino) acetylamino) butanoic acid
Dap (S) -2, 4-diaminopropionic acid
Dap(CONH2) (S) -2-amino-3-ureidopropionic acid
Dap(MeO(CH2)2) (S) -2-amino-3- (2-methoxyethylamino) propionic acid
Dap((MeO(CH2)2)2) (S) -2-amino-3- (bis (2-methoxyethyl) amino) propionic acid
Dab (Sar) (S) -2-amino-3- (2- (methylamino) acetylamino) propanoic acid
Deg 2-amino-2-ethylbutyric acid
Gly (tBu) (S) -2-amino-3, 3-dimethylbutyric acid
Gln (iBu) (S) -2-amino-5- (isobutylamino) -5-oxopentanoic acid
Gln (Me) (S) -2-amino-5- (methylamino) -5-oxopentanoic acid
Gln(Me2) (S) -2-amino-5- (dimethylamino) -5-oxopentanoic acid
Gln (iPr) (S) -2-amino-5- (isopropylamino) -5-oxopentanoic acid
Gln (cPr) (S) -2-amino-5- (cyclopropylamino) -5-oxopentanoic acid
Glu (Ala) (S) -2-amino-5- ((S) -1-carboxyethylamino) -5-oxopentanoic acid
Glu(DAla) (S) -2-amino-5- ((R) -1-carboxyethylamino) -5-oxopentanoic acid
Glu (Arg) (S) -2-amino-5- ((S) -1-carboxy-4-guanidinobutylamino) -5-oxopentanoic acid
Glu(DArg) (S) -2-amino-5- ((R) -1-carboxy-4-guanidinobutylamino) -5-oxopentanoic acid
Glu (Glu) (S) -2- ((S) -4-amino-4-carboxybutanamide) glutaric acid
Glu (Gly) -2-amino-5- (carboxymethylamino) -5-oxopentanoic acid
Glu (His) (S) -2-amino-5- ((S) -1-carboxy-2- (1H-imidazol-5-yl) ethylamino) -5-oxopentanoic acid
Glu (Leu) (S) -2-amino-5- ((S) -1-carboxy-3-methylbutylamino) -5-oxopentanoic acid
Glu(DLeu) (S) -2-amino-5- ((R) -1-carboxy-3-methylbutylamino) -5-oxopentanoic acid
Glu (2Nal) (S) -2-amino-5- ((S) -1-carboxy-2- (naphthalen-2-yl) ethylamino) -5-oxopentanoic acid
Glu (Sar) (S) -2-amino-5- ((carboxymethyl) (methyl) amino) -5-oxopentanoic acid
Glu (Trp) (S) -2-amino-5- ((S) -1-carboxy-2- (1H-indol-3-yl) ethylamino) -5-oxopentanoic acid
Glu(DTrp) (S) -2-amino-5- ((R) -1-carboxy-2- (1H-indol-3-yl) ethylamino) -5-oxopentanoic acid
hAla (1Im) (S) -2-amino-3- (1H-imidazol-1-yl) -butyric acid
hAla (2Im) (S) -2-amino-3- (1H-imidazol-2-yl) -butyric acid
hArg (S) -2-amino-6-guanidinohexanoic acid
hCha (S) -2-amino-4-cyclohexylbutyric acid
hCys (S) -2-amino-4-mercaptobutanoic acid
hHis (S) -2-amino-4- (1H-imidazol-5-yl) butanoic acid
hLys (S) -2, 7-diaminoheptanoic acid
h2Pal (S) -2-amino-4- (pyridin-2-yl) -butyric acid
h3Pal (S) -2-amino-3- (pyridin-3-yl) -butyric acid
h4Pal (S) -2-amino-3- (pyridin-4-yl) -butyric acid
hPhe (S) -2-amino-4-phenylbutyric acid
hSer (S) -2-amino-4-hydroxybutyric acid
hSer (Me) (S) -2-amino-4-methoxybutyric acid
hTRp (S) -2-amino-4- (1H-indol-3-yl) butanoic acid
hTyr (S) -2-amino-4- (4-hydroxyphenyl) butanoic acid
His (Me) -2-amino-3- (1-methyl-1H-imidazol-5-yl) propionic acid
His (Bn) (S) -2-amino-3- (1-benzyl-1H-imidazol-5-yl) propionic acid
Hyp (Bn) (2S,4R) -4- (benzyloxy) pyrrolidine-2-carboxylic acid
(4S) -Hyp (Bn) (2S, 4S) -4- (benzyloxy) pyrrolidine-2-carboxylic acid
Hyp (4BrBn) (2S,4R) -4- (4-bromobenzyloxy) pyrrolidine-2-carboxylic acid
Hyp (3CNBn) (2S,4R) -4- (3-cyanobenzyloxy) pyrrolidine-2-carboxylic acid
Hyp (4CNBn) (2S,4R) -4- (4-cyanobenzyloxy) pyrrolidine-2-carboxylic acid
Hyp (CONHPh) (2S,4R) -4- (Phenylcarbamoyloxy) pyrrolidine-2-carboxylic acid
Hyp (Ph) (2S,4R) -4-phenoxypyrrolidine-2-carboxylic acid
Lat (S) -2-amino-3- (2-aminopyrimidin-4-yl) propionic acid
Lys (Ac) (S) -6-acetamido-2-aminocaproic acid
Lys (Bz) (S) -2-amino-6-benzoylhexanoic acid
Lys (Me) -2-amino-6- (methylamino) hexanoic acid
Lys (Nic) (S) -2-amino-6- (nicotinamide) hexanoic acid
Lys ((5R) OH) (2S, 5R) -2, 6-diamino-5-hydroxycaproic acid
Lys (4Oxa) (S) -2-amino-3- (2-aminoethoxy) propionic acid
Met(O2) (S) -2-amino-4- (methylsulfonyl) butanoic acid
1Nal (S) -2-amino-3-naphthalen-1-ylpropionic acid
2Nal (S) -2-amino-3-naphthalen-2-ylpropionic acid
Nle (S) -2-amino-hexanoic acid
Nle (6OBn) (S) -2-amino-6- (benzyloxy) hexanoic acid
Octg (S) -2-aminodecanoic acid
Oic (2S, 3aS, 7aS) -octahydro-1H-indole-2-carboxylic acid
2Pal (S) -2-amino-3- (pyridin-2-yl) propionic acid
3Pal (S) -2-amino-3- (pyridin-3-yl) propionic acid
4Pal (S) -2-amino-3- (pyridin-4-yl) propionic acid
Phe (2Cl) (S) -2-amino-3- (2-chlorophenyl) propionic acid
Phe (3Cl) (S) -2-amino-3- (3-chlorophenyl) propionic acid
Phe (4Cl) (S) -2-amino-3- (4-chlorophenyl) propionic acid
Phe(3,4Cl2) (S) -2-amino-3- (3, 4-dichlorophenyl) propionic acid
Phe (2F) (S) -2-amino-3- (2-fluorophenyl) propionic acid
Phe (3F) (S) -2-amino-3- (3-fluorophenyl) propionic acid
Phe (4F) (S) -2-amino-3- (4-fluorophenyl) propionic acid
Phe (4CN) (S) -2-amino-3- (4-cyanophenyl) propionic acid
Phe(4CF3) (S) -2-amino-3- (4- (trifluoromethyl)) propionic acid
Phe (4COOMe) (S) -2-amino-3- (4- (methoxycarbonyl) phenyl) propanoic acid
Phg (S) -2-amino-2-phenylacetic acid
Pip (S) -piperidine-2-carboxylic acid
Pro ((4R)4BrBn) (2S,4R) -4- (4-bromobenzyl) pyrrolidine-2-carboxylic acid
Pro ((4R) Bn) (2S,4R) -4-benzylpyrrolidine-2-carboxylic acid
Pro ((4R)3CNBn) (2S,4R) -4- (3-cyanobenzyl) pyrrolidine-2-carboxylic acid
Pro ((4S) F) (2S, 4S) -4-fluoropyrrolidine-2-carboxylic acid
Pro ((4S) cHex) (2S, 4S) -4-cyclohexylpyrrolidine-2-carboxylic acid
Pro(5,5Me2) (S) -3, 3-dimethylpyrrolidine-2-carboxylic acid
Pro ((4R) Ph) (2S,4R) -4-phenylpyrrolidine-2-carboxylic acid
Ser (Bn) (S) -2-amino-3- (benzyloxy) propionic acid
Ser (Me) (S) -2-amino-3-methoxy-propionic acid
Thi (S) -2-amino-3- (thien-2-yl) propionic acid
alloThr (2S, 3S) -2-amino-3-hydroxybutyric acid
Thr (Bn) (2S, 3R) -2-amino-3- (benzyloxy) butyric acid
Thz (4R) -1, 3-thiazolidine-4-carboxylic acid
Thz(5,5Me2) (4R) -5, 5-dimethyl-1, 3-thiazolidine-4-carboxylic acid
Tic (3S) -1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
Tic (7OH) (3S) -7-hydroxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
DLTrp (7Aza) (RS) -2-amino-3- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) propionic acid
Trp (5Br) (S) -2-amino-3- (5-bromo-1H-indol-3-yl) propionic acid
Trp (6Br) (S) -2-amino-3- (6-bromo-1H-indol-3-yl) propionic acid
Trp(6CF3) (S) -2-amino-3- (6- (trifluoromethyl) -1H-indol-3-yl) propionic acid
Trp (5Cl) (S) -2-amino-3- (5-chloro-1H-indol-3-yl) propionic acid
Trp (6Cl) (S) -2-amino-3- (6-chloro-1H-indol-3-yl) propionic acid
Trp (5,6Cl) (S) -2-amino-3- (5, 6-dichloro-1H-indol-3-yl) propionic acid
Trp (5OH) (S) -2-amino-3- (5-hydroxy-1H-indol-3-yl) propionic acid
Tyr (Bn) (S) -2-amino-3- (4- (benzyloxy) phenyl) propionic acid
Tyr (Me) -2-amino-3- (4-methoxyphenyl) propionic acid
Tyr (4MeOCOBn) (S) -2-amino-3- (4- (4- (methoxycarbonyl) benzyloxy) phenyl) -propionic acid
Tyr (Ph) (S) -2-amino-3- (4-phenoxyphenyl) propionic acid
Tyr (4OHPh) (S) -2-amino-3- [4- (4-hydroxyphenoxy) phenyl ] propanoic acid
Tza (S) -2-amino-3- (thiazol-4-yl) propionic acid
Gln (Alk1) (S) -2-amino-5-oxo-5- (2,2, 2-trifluoroethylamino) pentanoic acid
Gln (Alk2) (S) -2-amino-5- (cyclopentylamino) -5-oxopentanoic acid
Gln (Alk3) (S) -2-amino-5- (cyclohexylamino) -5-oxopentanoic acid
Gln (Alk4) (S) -2-amino-5-oxo-5- (tetrahydro-2H-pyran-4-ylamino) pentanoic acid
Gln (Alk5) (S) -2-amino-5- (2-hydroxyethylamino) -5-oxopentanoic acid
Gln (Alk6) (S) -2-amino-5- (2-methoxyethylamino) -5-oxopentanoic acid
Gln (Alk7) (S) -2-amino-5- (2-aminoethylamino) -5-oxopentanoic acid
Gln (Alk8) (S) -2-amino-5- (2- (dimethylamino) ethylamino) -5-oxopentanoic acid
Gln (Alk9) (S) -2-amino-5- ((2-methoxyethyl) (methyl) amino) -5-oxopentanoic acid
Gln (Alk10) (S) -2-amino-5- ((2- (dimethylamino) ethyl) (methyl) amino) -5-oxopentanoic acid
Gln (Alk11) (S) -2-amino-5- (3-aminopropylamino) -5-oxopentanoic acid
Gln (Alk12) (S) -2-amino-5- (3- (dimethylamino) propylamino) -5-oxopentanoic acid
Gln (Alk13) (S) -2-amino-5- ((3- (dimethylamino) propyl) (methyl) amino) -5-oxopentanoic acid
Gln (Alk14) (S) -5- (3-acetamidopropylamino) -2-amino-5-oxopentanoic acid
Gln (Alk15) (S) -2-amino-5-oxo-5- (2- (pyrrolidin-1-yl) ethylamino) pentanoic acid
Gln (Alk16) (S) -2-amino-5- (2-morpholinoethylamino) -5-oxopentanoic acid
Gln (Alk17) (S) -2-amino-5- (3-morpholinopropylamino) -5-oxopentanoic acid
Gln (Alk18) (S) -2-amino-5- (1, 3-dihydroxypropan-2-ylamino) -5-oxopentanoic acid
Gln (Alk19) (S) -2-amino-5- (4-hydroxy-3- (hydroxymethyl) butylamino) -5-oxopentanoic acid
Gln (Alk20) (S) -2-amino-5-oxo-5- (piperidin-4-ylmethyl-amino) pentanoic acid
Gln (Alk21) (S) -2-amino-5- (methyl ((tetrahydro-2H-pyran-4-yl) methyl) amino) -5-oxopentanoic acid
Gln (Alk22) (2S) -2-amino-5- (methyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino) -5-oxopentanoic acid
Gln (Alk23) (S) -2-amino-5-oxo-5- (thiazol-2-ylmethylamino) pentanoic acid
Gln (Alk24) (S) -2-amino-5- ((1-methyl-1H-imidazol-4-yl) methylamino) -5-oxopentanoic acid
Gln (Alk25) (S) -2-amino-5- (benzylamino) -5-oxopentanoic acid
Gln (Alk26) (S) -2-amino-5- (4- (methylsulfonyl) benzylamino) -5-oxopentanoic acid
Gln (Alk27) (S) -2-amino-5-oxo-5- (pyridin-3-ylmethylamino) pentanoic acid
Gln (Alk28) (S) -2-amino-5-oxo-5- (4- (trifluoromethyl) benzylamino) pentanoic acid
Gln (Alk29) (S) -2-amino-5- (2-methoxybenzylamino) -5-oxopentanoic acid
Gln (Alk30) (S) -2-amino-5- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methylamino) -5-oxopentanoic acid
Gln (Alk31) (S) -2-amino-5- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) -methylamino) -5-oxopentanoic acid
Gln (Alk32) (S) -5- (2- (1H-indol-3-yl) ethylamino) -2-amino-5-
Oxopentanoic acid
Gln (Alk33) (2S) -2-amino-5- (2, 3-dihydro-1H-inden-1-ylamino) -5-oxo
Substituted valeric acid
Gln (Alk34) (2S) -2-amino-5-oxo-5- (1,2,3, 4-tetrahydronaphthalen-1-yl)
Amino) -pentanoic acid
Glu (cN1) (S) -2-amino-5- (azetidin-1-yl) -5-oxopentanoic acid
Glu (cN2) (S) -2-amino-5-oxo-5- (pyrrolidin-1-yl) pentanoic acid
Glu (cN3) (S) -2-amino-5-oxo-5- (piperidin-1-yl) pentanoic acid
Glu (cN4) (S) -2-amino-5-morpholino-5-oxopentanoic acid
Glu (cN5) (S) -2-amino-5-oxo-5- (piperazin-1-yl) pentanoic acid
Glu (cN6) (S) -2-amino-5- (4-methylpiperazin-1-yl) -5-oxopentanoic acid
Glu (cN7) (S) -2-amino-5- (4-hydroxypiperidin-1-yl) -5-oxopentanoic acid
Glu (cN8) (S) -2-amino-5- (4- (dimethylamino) piperidin-1-yl) -5-oxo
Substituted valeric acid
Glu (cN9) (2S) -2-amino-5- (7-methyl-1, 7-diazaspiro [4.4] nonane-
1-yl) -5-oxopentanoic acid
Glu (cN10) (S) -2-amino-5- (indolin-1-yl) -5-oxopentanoic acid
Glu (cN11) (S) -2-amino-5- (5, 6-dihydro-1, 7-naphthyridine-7 (8H) -
5-oxo-pentanoic acid
Glu (cN12) (S) -2-amino-5- (3, 4-dihydro-1, 5-naphthyridine-1 (2H) -
5-oxo-pentanoic acid
Glu (cN13) (S) -2-amino-5- (5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -
5-oxo-pentanoic acid
Glu (cN14) (S) -5- (4- (1H-imidazol-1-yl) piperidin-1-yl) -2-amino-5-
Oxopentanoic acid
Glu (cN15) (S) -5- (4- (1H-imidazol-2-yl) piperidin-1-yl) -2-amino-5-
Oxopentanoic acid
Glu (cN16) (S) -2-amino-5- (1, 4-oxazepin-4-yl) -5-oxopentanoic acid
Glu (cN17) (S) -2-amino-5- (4-methyl-1, 4-diazepin-1-yl) -5-
Oxopentanoic acid
Sab (N1) (S) -2-amino-4-sulfamoylbutyric acid
Sab (N2) (S) -2-amino-4- (N-methylsulfamoyl) butanoic acid
Sab (N3) (S) -2-amino-4- (N, N-dimethylsulfamoyl) butanoic acid
Sab (N4) (S) -2-amino-4- (N-isopropylsulfamoyl) butanoic acid
Sab (N5) (S) -2-amino-4- (N-cyclopropylsulfamoyl) butanoic acid
Sab (N6) (S) -2-amino-4- (N-isobutylsulfamoyl) butyric acid
Sab (N7) (S) -2-amino-4- (N- (2,2, 2-trifluoroethyl) sulfamoyl) butyric acid
Sab (N8) (S) -2-amino-4- (azetidin-1-ylsulfonyl) butanoic acid
Sab (N9) (S) -2-amino-4- (pyrrolidin-1-ylsulfonyl) butanoic acid
Sab (N10) (S) -2-amino-4- (piperidin-1-ylsulfonyl) butanoic acid
Sab (N11) (S) -2-amino-4- (morpholinosulfonyl) butanoic acid
Sab (N12) (S) -2-amino-4- (piperazin-1-ylsulfonyl) butanoic acid
Sab (N13) (S) -2-amino-4- (4-methylpiperazin-1-ylsulfonyl) butanoic acid
Sab (N14) (S) -4- (4-acetylpiperazin-1-ylsulfonyl) -2-aminobutanoic acid
Sab (N15) (S) -2-amino-4- (4-hydroxypiperidin-1-ylsulfonyl) butanoic acid
Sab (N16) (2S) -2-amino-4- (2-methyl-1-oxo-2, 6-diazaspiro [4.5]
Decan-6-ylsulfonyl) -butyric acid
Sab (N17) (S) -2-amino-4- (4- (dimethylamino) piperidin-1-ylsulfonyl)
Butyric acid
Sab (N18) (2S) -2-amino-4- (7-methyl-1, 7-diazaspiro [4.4] nonane-
1-ylsulfonyl) -butyric acid
Sab (N19) (S) -2-amino-4- (2, 2-dimethylpyrrolidin-1-ylsulfonyl) butanoic acid
Sab (N20) (S) -2-amino-4- (N-cyclopentylsulfamoyl) butanoic acid
Sab (N21) (S) -2-amino-4- (N-cyclohexylsulfamoyl) butanoic acid
Sab (N22) (S) -2-amino-4- (N- (tetrahydro-2N-pyran-4-yl) sulfamoyl)
Butyric acid
Sab (N23) (S) -2-amino-4- (N- (2-hydroxyethyl) sulfamoyl) butanoic acid
Sab (N24) (S) -2-amino-4-N- (2-methoxyethyl) sulfamoyl) butyric acid
Sab (N25) (S) -2-amino-4- (N- (2-aminoethyl) sulfamoyl) butanoic acid
Sab (N26) (S) -2-amino-4-N- (2- (dimethylamino) ethyl) sulfamoyl)
Butyric acid
Sab (N27) (S) -2-amino-4-N- (2-methoxyethyl) -N-methylsulfamoyl
Yl) butyric acid
Sab (N28) (S) -2-amino-4-N- (2- (dimethylamino) ethyl) -N-methyl
Sulfamoyl) -butyric acid
Sab (N29) (S) -2-amino-4- (N- (3-aminopropyl) sulfamoyl) butanoic acid
Sab (N30) (S) -2-amino-4- (N- (3- (dimethylamino) propyl) sulfamoyl
Yl) butyric acid
Sab (N31) (S) -2-amino-4- (N- (3- (dimethylamino) propyl) -N-methyl
Sulfamoyl) -butyric acid
Sab (N32) (S) -4- (N- (2-acetamidomethyl) sulfamoyl) -2-aminobutyric acid
Sab (N33) (S) -2-amino-4- (N- (2- (pyrrolidin-1-yl) ethyl) sulfamoyl)
Butyric acid
Sab (N34) (S) -2-amino-4- (N- (2-morpholinoethyl) sulfamoyl) butanoic acid
Sab (N35) (S) -2-amino-4- (N- (3-morpholinopropyl) sulfamoyl) butanoic acid
Sab (N36) (S) -2-amino-4- (N- (1, 3-dihydroxypropan-2-yl) sulfamoyl
Yl) butyric acid
Sab (N37) (S) -2-amino-4- (N- (4-hydroxy-3- (hydroxymethyl) butyl) amino
Sulfonyl) -butyric acid
Sab (N38) (S) -2-amino-4- (N- (piperidin-4-ylmethyl) sulfamoyl) butyric acid
Sab (N39) (S) -2-amino-4- (N-methyl-N- ((tetrahydro-2H-pyran-4-yl)
Methyl) -sulfamoyl) butyric acid
Sab (N40) (2S) -2-amino-4- (N-methyl-N- (2- (1-methylpyrrolidine-2-)
Yl) ethyl) -sulfamoyl) -butyric acid
Sab (N41) (S) -2-amino-4- (N- (thiazol-2-ylmethyl) sulfamoyl) butyric acid
Sab (N42) (S) -2-amino-4- (N- ((1-methyl-1H-imidazol-4-yl) methyl)
-sulfamoyl) butyric acid
Sab (N43) (S) -2-amino-4- (N-benzylsulfamoyl) butanoic acid
Sab (N44) (S) -2-amino-4- (N- (4- (methylsulfonyl) benzyl) sulfamoyl)
Butyric acid
Sab (N45) (S) -2-amino-4- (N- (pyridin-3-ylmethyl) sulfamoyl) butanoic acid
Sab (N46) (S) -2-amino-4- (N- (4- (trifluoromethyl) benzyl) sulfamoyl) butanoic acid
Sab (N47) (S) -2-amino-4- (N- (2-methoxybenzyl) -N-methylsulfamoyl
Yl) butyric acid
Sab (N48) (S) -2-amino-4- (N- ((1-methyl-1H-benzo [ d ] imidazole-2-)
Yl) methyl) -sulfamoyl) butyric acid
Sab (N49) (S) -2-amino-4- (N- ((4-methyl-6- (trifluoromethyl) pyrimidine-2-)
Yl) methyl) -sulfamoyl) butyric acid
Sab (N50) (S) -4- (N- (2- (1H-indol-2-yl) ethyl) sulfamoyl) -2-
Aminobutyric acid
Sab (N51) (S) -2-amino-4- (indolin-1-ylsulfonyl) butanoic acid
Sab (N52) (S) -2-amino-4- (5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl
Sulfonyl) -butyric acid
Sab (N53) (S) -2-amino-4- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl
Sulfonyl) -butyric acid
Sab (N54) (S) -2-amino-4- (5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -
Arylsulfonyl) -butyric acid
Sab (N55) (S) -4- (4- (1H-imidazol-1-yl) piperidin-1-ylsulfonyl) -2-
Aminobutyric acid
Sab (N56) (S) -4- (4- (1H-imidazol-2-yl) piperidin-1-ylsulfonyl) -2-amino
Butyric acid ester
Sab (N57) (S) -4- (1, 4-oxazepin-4-ylsulfonyl) -2-aminobutanoic acid
Sab (N58) (S) -2-amino-4- (4-methyl-1, 4-diazepin-1-ylsulfonyl)
Butyric acid
Sab (N59) (2S) -2-amino-4- (N- (2, 3-dihydro-1H-inden-1-yl) sulfamoyl
Yl) butyric acid
Sab (N60) (2S) -2-amino-4- (N- (1,2,3, 4-tetrahydronaphthalen-1-yl) sulfamoyl
Yl) -butyric acid
Sab (N61) (S) -2-amino-4- (4- (2-hydroxyethyl) piperazin-1-ylsulfonyl)
Butyric acid
Dab (SN1) (S) -2-amino-4- (sulfamoylamino) butanoic acid
Dab (SN2) (S) -2-amino-4- (N-methylsulfamoylamino) butanoic acid
Dab (SN3) (S) -2-amino-4- (N, N-Dimethylsulfamoylamino) butanoic acid
Dab (SN4) (S) -2-amino-4- (N-isopropylaminosulfonylamino) butanoic acid
Dab (SN5) (S) -2-amino-4- (N-cyclopropylsulfamoylamino) butanoic acid
Dab (SN6) (S) -2-amino-4- (N-isobutylsulfamoylamino) butanoic acid
Dab (SN7) (S) -2-amino-4- (N- (2,2, 2-trifluoroethyl) sulfamoylammonia
Yl) butyric acid
Dab (SN8) (S) -2-amino-4- (azetidin-1-ylsulfonylamino) butanoic acid
Dab (SN9) (S) -2-amino-4- (pyrrolidin-1-ylsulfonylamino) butanoic acid
Dab (SN10 (S) -2-amino-4- (piperidin-1-ylsulfonylamino) butanoic acid
Dab (SN11) (S) -2-amino-4- (morpholinosulfonylamino) butanoic acid
Dab (SN12) (S) -2-amino-4- (piperazin-1-ylsulfonylamino) butanoic acid
Dab (SN13) (S) -2-amino-4- (4-methylpiperazin-1-ylsulfonylamino) butanoic acid
Dab (SN14) (S) -4- (4-Acetylpiperazin-1-ylsulfonylamino) -2-aminobutanoic acid
Dab (SN15) (S) -2-amino-4- (4-hydroxypiperidin-1-ylsulfonylamino) butanoic acid
Dab (SN16) (2S) -2-amino-4- (2-methyl-1-oxo-2, 6-diazaspiro [4.5]
Decan-6-yl-sulfonylamino) butanoic acid
Dab (SN17) (S) -2-amino-4- (4- (dimethylamino) piperidin-1-ylsulfonyl)
Amino) -butyric acid
Dab (SN18) (2S) -2-amino-4- (7-methyl-1, 7-diazaspiro [4.4] nonane-
1-ylsulfonylamino) -butyric acid
Dab (SN19) (S) -2-amino-4- (2, 2-dimethylpyrrolidin-1-ylsulfonylamino)
Yl) butyric acid
Dab (SN20) (S) -2-amino-4- (N-cyclopentylsulfamoylamino) butanoic acid
Dab (SN21) (S) -2-amino-4- (N-cyclohexylsulfamoylamino) butanoic acid
Dab (SN22) (S) -2-amino-4- (N- (tetrahydro-2H-pyran-4-yl) sulfamoyl
Amino) butyric acid
Dab (SN23) (S) -2-amino-4- (N- (2-hydroxyethyl) sulfamoylamino) butanoic acid
Dab (SN24) (S) -2-amino-4- (N- (2-methoxyethyl) sulfamoylamino)
Butyric acid
Dab (SN25) (S) -2-amino-4- (N- (2-aminoethyl) sulfamoylamino) butanoic acid
Dab (SN26) (S) -2-amino-4- (N- (2- (dimethylamino) ethyl) sulfamoyl
Amino) butyric acid
Dab (SN27) (S) -2-amino-4- (N- (2-methoxyethyl) -N-methylsulfamoyl)
Alkylamino) -butyric acid
Dab (SN28) (S) -2-amino-4- (N- (2- (dimethylamino) ethyl) -N-methyl
Sulfamoylamino) -butyric acid
Dab (SN29) (S) -2-amino-4- (N- (3-aminopropyl) sulfamoylamino) butanoic acid
Dab (SN30) (S) -2-amino-4- (N- (3- (dimethylamino) propyl) sulfamoyl
Alkylamino) butanoic acid
Dab (SN31) (S) -2-amino-4- (N- (3- (dimethylamino) propyl) -N-methyl
Sulfamoylamino) -butyric acid
Dab (SN32) (S) -4- (N- (2-Acetaminoethyl) sulfamoylamino) -2-amino
Butyric acid ester
Dab (SN33) (S) -2-amino-4- (N- (2- (pyrrolidin-1-yl) ethyl) sulfamoyl
Alkylamino) butanoic acid
Dab (SN34) (S) -2-amino-4- (N- (2-morpholinoethyl) sulfamoylamino)
Butyric acid
Dab (SN35) (S) -2-amino-4- (N- (3-morpholinopropyl) sulfamoylamino)
Butyric acid
Dab (SN36) (S) -2-amino-4- (N- (1, 3-dihydroxypropan-2-yl) sulfamoyl
Alkylamino) -butyric acid
Dab (SN37) (S) -2-amino-4- (N- (4-hydroxy-3- (hydroxymethyl) butyl) -
Sulfamoylamino) butanoic acid
Dab (SN38) (S) -2-amino-4- (N- (piperidin-4-ylmethyl) sulfamoylamino)
Butyric acid
Dab (SN39) (S) -2-amino-4- (N-methyl-N- ((tetrahydro-2H-pyran-4-yl)
Methyl) -sulfamoylamino) butanoic acid
Dab (SN40) (2S) -2-amino-4- (N-methyl-N- (2- (1-methylpyrrolidine-2-)
Yl) ethyl) -sulfamoylamino) butanoic acid
Dab (SN41) (S) -2-amino-4- (N- (thiazol-2-ylmethyl) sulfamoylammonia
Yl) butyric acid
Dab (SN42) (S) -2-amino-4- (N- ((1-methyl-1H-imidazol-4-yl) methyl) -
Sulfamoylamino) butanoic acid
Dab (SN43) (S) -2-amino-4- (N-benzylsulfamoylamino) butanoic acid
Dab (SN44) (S) -2-amino-4- (N- (4- (methylsulfonyl) benzyl) sulfamoyl
Alkylamino) butanoic acid
Dab (SN45) (S) -2-amino-4- (N- (pyridin-3-ylmethyl) sulfamoylamino)
Butyric acid
Dab (SN46) (S) -2-amino-4- (N- (4- (trifluoromethyl) benzyl) sulfamoyl
Amino) butyric acid
Dab (SN47) (S) -2-amino-4- (N- (2-methoxybenzyl) -N-methylsulfamoyl)
Alkylamino) -butyric acid
Dab (SN48) (S) -2-amino-4- (N- ((1-methyl-1H-benzo [ d ] imidazole-2-)
Yl) methyl) -sulfamoylamino) butanoic acid
Dab (SN49) (S) -2-amino-4- (N- ((4-methyl-6- (trifluoromethyl) pyrimidine-
2-yl) methyl) -sulfamoylamino) butanoic acid
Dab (SN50) (S) -4- (N- (2- (1H-indol-2-yl) ethyl) sulfamoylamino)
-2-aminobutyric acid
Dab (SN51) (S) -2-amino-4- (indolin-1-ylsulfonylamino) butanoic acid
Dab (SN52) (S) -2-amino-4- (5,6,7, 8-tetrahydro-1, 7-naphthyridine-7-
Sulfonamido) -butyric acid
Dab (SN53) (S) -2-amino-4- (1,2,3, 4-tetrahydro-1, 5-naphthyridine-1-
Sulfonamido) -butyric acid
Dab (SN54) (S) -2-amino-4- (5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine-
7-sulfonamido) -butyric acid
Dab (SN55) (S) -4- (4- (1H-imidazol-1-yl) piperidin-1-ylsulfonylamino)
-2-aminobutyric acid
Dab (SN56) (S) -4- (4- (1H-imidazol-2-yl) piperidin-1-ylsulfonylamino)
-2-aminobutyric acid
Dab (SN57) (S) -4- (1, 4-Oxoazepin-4-ylsulfonylamino) -2-amino
Butyric acid
Dab (SN58) (S) -2-amino-4- (4-methyl-1, 4-diazepin-1-ylsulfonyl)
Alkylamino) butanoic acid
Dab (SN59) (2S) -2-amino-4- (N- (2, 3-dihydro-1H-inden-1-ylamino)
Sulfamoyl) -butyric acid
Dab (SN60) (2S) -2-amino-4- (N- (1,2,3, 4-tetrahydronaphthalen-1-yl) sulfamate
Acylamino) -butyric acid
Dab (SN61) (S) -2-amino-4- (4- (2-hydroxyethyl) piperazine-1-sulfinamide
Yl) butyric acid
Dab (UN1) (S) -2-amino-4-ureidobutanoic acid
Dab (UN2) (S) -2-amino-4- (3-methylureido) butanoic acid
Dab (UN3) (S) -2-amino-4- (3, 3-dimethylureido) butanoic acid
Dab (UN4) (S) -2-amino-4- (3-isopropylureido) butanoic acid
Dab (UN5) (S) -2-amino-4- (3-cyclopropylureido) butanoic acid
Dab (UN6) (S) -2-amino-4- (3-isobutylureido) butanoic acid
Dab (UN7) (S) -2-amino-4- (3- (2,2, 2-trifluoroethyl) ureido) butanoic acid
Dab (UN8) (S) -2-amino-4- (azetidine-1-carboxyamino) butanoic acid
Dab (UN9) (S) -2-amino-4- (pyrrolidine-1-carboxyamino) butanoic acid
Dab (UN10) (S) -2-amino-4- (piperidine-1-carboxyamino) butanoic acid
Dab (UN11) (S) -2-amino-4- (morpholine-4-carboxyamino) butanoic acid
Dab (UN12) (S) -2-amino-4- (piperazine-1-carboxyamino) butanoic acid
Dab (UN13) (S) -2-amino-4- (4-methylpiperazine-1-carboxyamino) butanoic acid
Dab (UN14) (S) -4- (4-acetylpiperazine-1-carboxyamino) -2-aminobutyric acid
Dab (UN15) (S) -2-amino-4- (4-hydroxypiperidine-1-carboxyamino) butanoic acid
Dab (UN16) (2S) -2-amino-4- (2-methyl-1-oxo-2, 6-diazaspiro [4.5]
Decane-6-carboxyamino) butyric acid
Dab (UN17) (S) -2-amino-4- (4- (dimethylamino) piperidine-1-carboxyamino)
Butyric acid
Dab (UN18) (2S) -2-amino-4- (7-methyl-1, 7-diazaspiro [4.4] nonane-
1-carboxyamino) -butyric acid
Dab (UN19) (S) -2-amino-4- (2, 2-dimethylpyrrolidine-1-carboxyamino) butanoic acid
Dab (UN20) (S) -2-amino-4- (3-cyclopentylureido) butanoic acid
Dab (UN21) (S) -2-amino-4- (3-cyclohexylureido) butanoic acid
Dab (UN22) (S) -2-amino-4- (3- (tetrahydro-2H-pyran-4-yl) ureido) butanoic acid
Dab (UN23) (S) -2-amino-4- (3- (2-hydroxyethyl) ureido) butanoic acid
Dab (UN24) (S) -2-amino-4- (3- (2-methoxyethyl) ureido) butanoic acid
Dab (UN25) (S) -2-amino-4- (3- (2-aminoethyl) ureido) butanoic acid
Dab (UN26) (S) -2-amino-4- (3- (2- (dimethylamino) ethyl) ureido) butanoic acid
Dab (UN27) (S) -2-amino-4- (3- (2-methoxyethyl) -N-methylureido) butanoic acid
Dab (UN28) (S) -2-amino-4- (3- (2- (dimethylamino) ethyl) -N-methyl
Ureido) butanoic acid
Dab (UN29) (S) -2-amino-4- (3- (3-aminopropyl) ureido) butanoic acid
Dab (UN30) (S) -2-amino-4- (3- (3- (dimethylamino) propyl) ureido) butanoic acid
Dab (UN31) (S) -2-amino-4- (3- (3- (dimethylamino) propyl) -N-methyl
Ureido) butanoic acid
Dab (UN32) (S) -4- (3- (2-Acetaminoethyl) ureido) -2-aminobutanoic acid
Dab (UN33) (S) -2-amino-4- (3- (2- (pyrrolidin-1-yl) ethyl) ureido) butanoic acid
Dab (UN34) (S) -2-amino-4- (3- (2-morpholinoethyl) ureido) butanoic acid
Dab (UN35) (S) -2-amino-4- (3- (3-morpholinopropyl) ureido) butanoic acid
Dab (UN36) (S) -2-amino-4- (3- (1, 3-dihydroxypropan-2-yl) ureido) butanoic acid
Dab (UN37) (S) -2-amino-4- (3- (4-hydroxy-3- (hydroxymethyl) butyl) urea
Yl) butyric acid
Dab (UN38) (S) -2-amino-4- (3- (piperidin-4-ylmethyl) ureido) butanoic acid
Dab (UN39) (S) -2-amino-4- (3-methyl-3- ((tetrahydro-2H-pyran-4-yl)
Methyl) ureido) -butyric acid
Dab (UN40) (2S) -2-amino-4- (3-methyl-3- (2- (1-methylpyrrolidine-2-)
Yl) ethyl) ureido) -butyric acid
Dab (UN41) (S) -2-amino-4- (3- (thiazol-2-ylmethyl) ureido) butanoic acid
Dab (UN42) (S) -2-amino-4- (3- ((1-methyl-1H-imidazol-4-yl) methyl)
Ureido) butanoic acid
Dab (UN43) (S) -2-amino-4- (3-benzylureido) butanoic acid
Dab (UN44) (S) -2-amino-4- (3- (4- (methylsulfonyl) benzyl) ureido) butanoic acid
Dab (UN45) (S) -2-amino-4- (3- (pyridin-3-ylmethyl) ureido) butanoic acid
Dab (UN46) (S) -2-amino-4- (3- (4- (trifluoromethyl) benzyl) ureido) butanoic acid
Dab (UN47) (S) -2-amino-4- (3- (2-methoxybenzyl) -3-methylureido) butanoic acid
Dab (UN48) (S) -2-amino-4- (3- ((1-methyl-1H-benzo [ d ] imidazole-2-)
Yl) methyl) ureido) -butyric acid
Dab (UN49) (S) -2-amino-4- (3- ((4-methyl-6- (trifluoromethyl) pyrimidine-
2-yl) methyl) -ureido) butanoic acid
Dab (UN50) (S) -4- (3- (2- (1H-indol-2-yl) ethyl) ureido) -2-aminobutanoic acid
Dab (UN51) (S) -2-amino-4- (indoline-1-carboxyamino) butanoic acid
Dab (UN52) (S) -2-amino-4- (5,6,7, 8-tetrahydro-1, 7-naphthyridine-7-
Carboxy amino) -butyric acid
Dab (UN53) (S) -2-amino-4- (1,2,3, 4-tetrahydro-1, 5-naphthyridine-1-carboxylic acid
Alkylamino) -butyric acid
Dab (UN54) (S) -2-amino-4- (5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine-
7-carboxyamino) -butyric acid
Dab (UN55) (S) -4- (4- (1H-imidazol-1-yl) piperidin-1-ylamino) -2-amino
Butyric acid ester
Dab (UN56) (S) -4- (4- (1H-imidazol-2-yl) piperidin-1-carboxyamino) -2-
Aminobutyric acid
Dab (UN57) (S) -4- (1, 4-Oxazepin-4-carboxyamino) -2-aminobutanoic acid
Dab (UN58) (S) -2-amino-4- (4-methyl-1, 4-diazepine-1-carboxamidine
Yl) butyric acid
Dab (UN59) (2S) -2-amino-4- (3- (2, 3-dihydro-1H-inden-1-yl) ureido)
Butyric acid
Dab (UN60) (2S) -2-amino-4- (3- (1,2,3, 4-tetrahydronaphthalen-1-yl) ureido) -
Butyric acid
Dab (UN61) (S) -2-amino-4- (4- (2-hydroxyethyl) piperazine-1-carboxyamino)
Butyric acid
Dab (S1) (S) -2-amino-4- (methylsulphonamido) butanoic acid
Dab (S2) (S) -2-amino-4- (ethylsulfonamido) butanoic acid
Dab (S3) (S) -2-amino-4- (1-methylethylsulfonamido) butanoic acid
Dab (S4) (S) -2-amino-4- (cyclopropanesulfonamido) butanoic acid
Dab (S5) (S) -2-amino-4- (2-methylpropylsulfonamido) butanoic acid
Dab (S6) (S) -2-amino-4- (2,2, 2-trifluoroethylsulfonamido) butanoic acid
Dab (S7) (S) -2-amino-4- (cyclopentanesulfonamido) butanoic acid
Dab (S8) (S) -2-amino-4- (Cyclohexanesulphonamido) butanoic acid
Dab (S9) (S) -2-amino-4- (tetrahydro-2H-pyran-4-sulfonamido) butanoic acid
Dab (S10) (S) -2-amino-4- (phenylsulphonamido) butanoic acid
Dab (S11) (S) -2-amino-4- (4-aminophenylsulfonamido) butanoic acid
Dab (S12) (S) -2-amino-4- (4- (dimethylamino) phenylsulphonamido) butanoic acid
Dab (S13) (S) -2-amino-4- (4-morpholinophenylsulphonamido) butanoic acid
Dab (S14) (S) -2-amino-4- (4-cyanophenylsulfonamido) butanoic acid
Dab (S15) (S) -2-amino-4- (5-cyanopyridine-2-sulfonamido) butanoic acid
Dab (S16) (S) -2-amino-4- (1H-pyrazole e-4-sulfonamido) butanoic acid
Dab (S17) (S) -2-amino-4- (1H-1,2, 4-triazole-5-sulfonamido) butanoic acid
Dab (S18) (S) -2-amino-4- (1, 1-Dimethylethylsulfonamido) butanoic acid
Dab (A1) (S) -4-acetylamino-2-aminobutanoic acid
Dab (A2) (S) -2-amino-4-propionamidobutyric acid
Dab (A3) (S) -2-amino-4-isobutyramide butyric acid
Dab (A4) (S) -2-amino-4- (cyclopropanecarbonylamino) butanoic acid
Dab (A5) (S) -2-amino-4- (3,3, 3-trifluoropropionamide) butyric acid
Dab (A6) (S) -2-amino-4- (4,4, 4-trifluorobutanamide) butanoic acid
Dab (A7) (S) -2-amino-4- (3-aminopropionamide) butyric acid
Dab (A8) (S) -2-amino-4- (4-aminobutanamide) butanoic acid
Dab (A9) (S) -2-amino-4- (5-aminopentanamide) butanoic acid
Dab (A10) (S) -2-amino-4- (3-methoxypropionamide) butyric acid
Dab (A11) (S) -2-amino-4- (3- (methylamino) propionamide) butanoic acid
Dab (A12) (S) -2-amino-4- (3- (dimethylamino) propionamide) butanoic acid
Dab (A13) (S) -2-amino-4- (3- (phenylamino) propanamide) butanoic acid
Dab (A14) (2S) -2-amino-4- (3-aminobutanamide) butanoic acid
Dab (A15) (S) -2-amino-4- (3-amino-3-methylbutyramide) butyric acid
Dab (A16) (S) -2-amino-4- (3- (methylsulfonyl) propanamide) butanoic acid
Dab (A17) (S) -2-amino-4- (2-cyclopropylacetamido) butanoic acid
Dab (A18) (2S) -2-amino-4- (2- (pyrrolidin-3-yl) acetylamino) butanoic acid
Dab (A19) (2S) -2-amino-4- (2- (pyrrolidin-2-yl) acetylamino) butanoic acid
Dab (A20) (S) -2-amino-4- (2- (piperidin-4-yl) acetylamino) butanoic acid
Dab (A21) (2S) -2-amino-4- (2- (piperidin-3-yl) acetylamino) butanoic acid
Dab (A22) (2S) -2-amino-4- (2- (piperidin-2-yl) acetylamino) butanoic acid
Dab (A23) (S) -2-amino-4- (3- (piperidin-1-yl) propanamide) butanoic acid
Dab (A24) (S) -2-amino-4- (3- (piperazin-1-yl) propionamide) butanoic acid
Dab (A25) (S) -2-amino-4- (3- (4-methylpiperazin-1-yl) propionamide) butanoic acid
Dab (A26) (S) -2-amino-4- (3-morpholinopropionamide) butanoic acid
Dab (A27) (S) -2-amino-4- (2- (1-aminocyclohexyl) acetylamino) butanoic acid
Dab (A28) (S) -2-amino-4- (2- (4-aminotetrahydro-2H-pyran-4-yl) ethyl
Amido) -butyric acid
Dab (A29) (2S) -2-amino-4- (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid
Alkylamino) butanoic acid
Dab (A30) (S) -2-amino-4-benzamidobutyric acid
Dab (A31) (S) -2-amino-4- (isonicotinamide) butanoic acid
Dab (A32) (S) -2-amino-4- (nicotinamide) butanoic acid
Dab (A33) (S) -2-amino-4- (picolinamide) butanoic acid
Dab (A34) (S) -2-amino-4- (6- (trifluoromethyl) nicotinamide) butanoic acid
Dab (A35) (S) -2-amino-4- (3-methoxybenzamide) butanoic acid
Dab (A36) (S) -2-amino-4- (3- (difluoromethoxy) benzamide) butanoic acid
Dab (A37) (S) -2-amino-4- (4- (methylsulfonyl) benzamide) butanoic acid
Dab (A38) (S) -2-amino-4- (benzo [ d ] [1,3] dioxol-5-)
Carboxy amino) butyric acid
Dab (A39) (S) -2-amino-4- (2- (pyridin-3-yl) acetylamino) butanoic acid
Dab (A40) (S) -2-amino-4- (pyrimidine-4-carboxyamino) butanoic acid
Dab (A41) (S) -2-amino-4- (3-cyanobenzamide) butanoic acid
Dab (A42) (S) -2-amino-4- (thiophene e-2-carboxyamino) butanoic acid
Dab (A43) (S) -2-amino-4- (1-methyl-1H-pyrrole-2-carboxyamino) butanoic acid
Dab (A44) (S) -2-amino-4- (thiazole-2-carboxyamino) butanoic acid
Dab (A45) (S) -2-amino-4- (thiazole-4-carboxyamino) butanoic acid
Dab (A46) (S) -2-amino-4- (1-methyl-1H-imidazole e-2-carboxyamino) butanoic acid
Dab (A47) (S) -2-amino-4- (1-methyl-1H-imidazole e-5-carboxyamino) butanoic acid
Dab (A48) (S) -2-amino-4- (1-methyl-1H-indole-2-carboxyamino) butanoic acid
Dab (A49) (S) -2-amino-4- (benzo [ d ] thiazole-2-carboxyamino) butanoic acid
Dab (A50) (S) -2-amino-4- (quinoxaline-2-carboxyamino) butyric acid
Dab (A51) (S) -4- (3- (1H-indol-3-yl) propionamide) -2-aminobutyric acid
Dab (A52) (S) -2-amino-4- (2-aminothiazole-4-carboxyamino) butanoic acid
Dab (A53) (S) -2-amino-4- (2- (2-aminothiazol-4-yl) acetylamino) butanoic acid
Dab (A54) (S) -2-amino-4- (4-guanidinobutanamide) butanoic acid
Dab (A55) (S) -2-amino-4- ((1H-imidazol-4-yl) methylamino) butanoic acid
Dab (A56) (S) -2-amino-4- (3- (1-methyl-1H-imidazol-5-yl) propanamide)
Butyric acid
Dab (Suc1) (S) -2-amino-4- (4- (methylamino) -4-oxobutanamide) butanoic acid
Dab (Suc2) (S) -2-amino-4- (4- (dimethylamino) -4-oxobutanamide) butanoic acid
Dab (Suc3) (S) -2-amino-4- (4-morpholino-4-oxobutanamide) butanoic acid
Dab (Suc4) (S) -2-amino-4- (4-oxo-4- (piperazin-1-yl) butanamide) butanoic acid
Dab (Suc5) (S) -2-amino-4- (4- (4-methylpiperazin-1-yl) -4-oxobutan
Amide) butyric acid
Dab (Suc6) (S) -2-amino-4- (4- (methylsulfinylamido) -4-oxobutan
Amide) butyric acid
Dab (Suc7) (S) -2-amino-4- (4- (1, 1-Dimethylethylsulfonamido) -
4-oxobutanamide) -butyric acid
Dab (Suc8) (S) -2-amino-4- (4-oxo-4- (phenylsulphonamido) butyryl
Amine) butyric acid
Dab (Suc9) (S) -2-amino-4- (4- (4-chloropyridine-3-sulfonamido) -4-
Oxobutanamide) -butyric acid
Dab (Suc10) (S) -2-amino-4- (4- (naphthalene-2-sulfonamido) -4-oxobutanoyl
Amine) -butyric acid
Asn (Alk1) (S) -2-amino-4-oxo-4- (2,2, 2-trifluoroethylamino) butanoic acid
Asn (Alk2) (S) -2-amino-4- (cyclopentylamino) -4-oxobutanoic acid
Asn (Alk3) (S) -2-amino-4- (cyclohexylamino) -4-oxobutanoic acid
Asn (Alk4) (S) -2-amino-4-oxo-4- (tetrahydro-2H-pyran-4-ylamino) butanoic acid
Asn (Alk5) (S) -2-amino-4- (2-hydroxyethylamino) -4-oxobutanoic acid
Asn (Alk6) (S) -2-amino-4- (2-methoxyethylamino) -4-oxobutanoic acid
Asn (Alk7) (S) -2-amino-4- (2-aminoethylamino) -4-oxobutanoic acid
Asn (Alk8) (S) -2-amino-4- (2- (dimethylamino) ethylamino) -4-oxo
Butyric acid
Asn (Alk9) (S) -2-amino-4- ((2-methoxyethyl) (methyl) amino) -4-oxo
Substituted butyric acid
Asn (Alk10) (S) -2-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -4-oxobutanoic acid
Asn (Alk11) (S) -2-amino-4- (3-aminopropylamino) -4-oxobutanoic acid
Asn (Alk12) (S) -2-amino-4- (3- (dimethylamino) propylamino) -4-oxobutanoic acid
Asn (Alk13) (S) -2-amino-4- ((3- (dimethylamino) propyl) (methyl) amino) -4-oxobutanoic acid
Asn (Alk14) (S) -4- (3-acetamidopropylamino) -2-amino-4-oxobutanoic acid
Asn (Alk15) (S) -2-amino-4-oxo-4- (2- (pyrrolidin-1-yl) ethylamino) butanoic acid
Asn (Alk16) (S) -2-amino-4- (2-morpholinoethylamino) -4-oxobutanoic acid
Asn (Alk17) (S) -2-amino-4- (3-morpholinopropylamino) -4-oxobutanoic acid
Asn (Alk18) (S) -2-amino-4- (1, 3-dihydroxypropan-2-ylamino) -4-oxobutanoic acid
Asn (Alk19) (S) -2-amino-4- (4-hydroxy-3- (hydroxymethyl) butylamino) -4-oxobutanoic acid
Asn (Alk20) (S) -2-amino-4-oxo-4- (piperidin-4-ylmethylamino) butanoic acid
Asn (Alk21) (S) -2-amino-4- (methyl ((tetrahydro-2H-pyran-4-yl) methyl) amino) -4-oxobutanoic acid
Asn (Alk22) (2S) -2-amino-4- (methyl (2- (1-methylpyrrolidin-2-yl) ethyl) amino) -4-oxobutanoic acid
Asn (Alk23) (S) -2-amino-4-oxo-4- (thiazol-2-ylmethylamino) butanoic acid
Asn (Alk24) (S) -2-amino-4- ((1-methyl-1H-imidazol-4-yl) methylamino) -4-oxobutanoic acid
Asn (Alk25) (S) -2-amino-4- (benzylamino) -4-oxobutanoic acid
Asn (Alk26) (S) -2-amino-4- (4- (methylsulfonyl) benzylamino) -4-oxobutanoic acid
Asn (Alk27) (S) -2-amino-4-oxo-4- (pyridin-3-ylmethylamino) butanoic acid
Asn (Alk28) (S) -2-amino-4-oxo-4- (4- (trifluoromethyl) benzylamino) butanoic acid
Asn (Alk29) (S) -2-amino-4- (2-methoxybenzylamino) -4-oxobutanoic acid
Asn (Alk30) (S) -2-amino-4- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methylamino) -4-oxobutanoic acid
Asn (Alk31) (S) -2-amino-4- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) -methylamino) -4-oxobutanoic acid
Asn (Alk32) (S) -4- (2- (1H-indol-3-yl) ethylamino) -2-amino-4-oxobutanoic acid
Asn (Alk33) (2S) -2-amino-4- (2, 3-dihydro-1H-inden-1-ylamino) -4-oxobutanoic acid
Asn (Alk34) (2S) -2-amino-4-oxo-4- (1,2,3, 4-tetrahydronaphthalen-1-ylamino) -butyric acid
Asp (cN1) (S) -2-amino-4- (azetidin-1-yl) -4-oxobutanoic acid
Asp (cN2) (S) -2-amino-4-oxo-4- (pyrrolidin-1-yl) butyric acid
Asp (cN3) (S) -2-amino-4-oxo-4- (piperidin-1-yl) butyric acid
Asp (cN4) (S) -2-amino-4-morpholino-4-oxobutanoic acid
Asp (cN5) (S) -2-amino-4-oxo-4- (piperazin-1-yl) butyric acid
Asp (cN6) (S) -2-amino-4- (4-methylpiperazin-1-yl) -4-oxobutanoic acid
Asp (cN7) (S) -2-amino-4- (4-hydroxypiperidin-1-yl) -4-oxobutanoic acid
Asp (cN8) (S) -2-amino-4- (4- (dimethylamino) piperidin-1-yl) -4-oxobutanoic acid
Asp (cN9) (2S) -2-amino-4- (7-methyl-1, 7-diazaspiro [4.4] nonan-1-yl) -4-oxobutanoic acid
Asp (cN10) (S) -2-amino-4- (indolin-1-yl) -4-oxobutanoic acid
Asp (cN11) (S) -2-amino-4- (5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -4-oxobutanoic acid
Asp (cN12) (S) -2-amino-4- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -4-oxobutanoic acid
Asp (cN13) (S) -2-amino-4- (5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) -4-oxobutanoic acid
Asp (cN14) (S) -4- (4- (1H-imidazol-1-yl) piperidin-1-yl) -2-amino-4-oxobutanoic acid
Asp (cN15) (S) -4- (4- (1H-imidazol-2-yl) piperidin-1-yl) -2-amino-4-oxobutanoic acid
Asp (cN16) (S) -2-amino-4- (1, 4-oxazepin-4-yl) -4-oxobutanoic acid
Asp (cN17) (S) -2-amino-4- (4-methyl-1, 4-diazepin-1-yl) -4-oxobutanoic acid
Sap (N1) (R) -2-amino-3-sulfamoylpropionic acid
Sap (N2) (R) -2-amino-3- (N-methylsulfamoyl) propionic acid
Sap (N3) (R) -2-amino-3- (N, N-dimethylsulfamoyl) propionic acid
Sap (N4) (R) -2-amino-3-N-isopropylsulfamoyl) propionic acid
Sap (N5) (R) -2-amino-3-N-cyclopropylsulfamoyl) propionic acid
Sap (N6) (R) -2-amino-3-N-isobutylsulfamoyl) propionic acid
Sap (N7) (R) -2-amino-3- (N- (2,2, 2-trifluoroethyl) sulfamoyl) propionic acid
Sap (N8) (R) -2-amino-3- (azetidin-1-ylsulfonyl) propionic acid
Sap (N9) (R) -2-amino-3- (pyrrolidin-1-ylsulfonyl) propionic acid
Sap (N10) (R) -2-amino-3- (piperidin-1-ylsulfonyl) propionic acid
Sap (N11) (R) -2-amino-3- (morpholinosulfonyl) propionic acid
Sap (N12) (R) -2-amino-3- (piperazin-1-ylsulfonyl) propionic acid
Sap (N13) (R) -2-amino-3- (4-methylpiperazin-1-ylsulfonyl) propionic acid
Sap (N14) (R) -3- (4-acetylpiperazin-1-ylsulfonyl) -2-aminopropionic acid
Sap (N15) (R) -2-amino-3- (4-hydroxypiperidin-1-ylsulfonyl) propionic acid
Sap (N16) (2R) -2-amino-3- (2-methyl-1-oxo-2, 6-diazaspiro [4.5] decan-6-ylsulfonyl) -propionic acid
Sap (N17) (R) -2-amino-3- (4- (dimethylamino) piperidin-1-ylsulfonyl) propionic acid
Sap (N18) (2R) -2-amino-3- (7-methyl-1, 7-diazaspiro [4.4] nonan-1-ylsulfonyl) -propionic acid
Sap (N19) (R) -2-amino-3- (2, 2-dimethylpyrrolidin-1-ylsulfonyl) propionic acid
Sap (N20) (R) -2-amino-3-N-cyclopentylsulfamoyl) propionic acid
Sap (N21) (R) -2-amino-3-N-cyclohexylsulfamoyl) propionic acid
Sap (N22) (R) -2-amino-3- (N- (tetrahydro-2H-pyran-4-yl) sulfamoyl) propionic acid
Sap (N23) (R) -2-amino-3- (N- (2-hydroxyethyl) sulfamoyl) propionic acid
Sap (N24) (R) -2-amino-3- (N- (2-methoxyethyl) sulfamoyl) propionic acid
Sap (N25) (R) -2-amino-3- (N- (2-aminoethyl) sulfamoyl) propionic acid
Sap (N26) (R) -2-amino-3- (N- (2- (dimethylamino) ethyl) sulfamoyl) propionic acid
Sap (N27) (R) -2-amino-3- (N- (2-methoxyethyl) -N-methylsulfamoyl) propionic acid
Sap (N28) (R) -2-amino-3- (N- (2- (dimethylamino) ethyl) -N-methylsulfamoyl) -propionic acid
Sap (N29) (R) -2-amino-3- (N- (3-aminopropyl) sulfamoyl) propionic acid
Sap (N30) (R) -2-amino-3- (N- (3- (dimethylamino) propyl) sulfamoyl) propionic acid
Sap (N31) (R) -2-amino-3- (N- (3- (dimethylamino) propyl) -N-methylsulfamoyl) -propionic acid
Sap (N32) (R) -3- (N- (2-acetamidoethyl) sulfamoyl) -2-aminopropionic acid
Sap (N33) (R) -2-amino-3- (N- (2- (pyrrolidin-1-yl) ethyl) sulfamoyl) propionic acid
Sap (N34) (R) -2-amino-3- (N- (2-morpholinoethyl) sulfamoyl) propionic acid
Sap (N35) (R) -2-amino-3- (N- (3-morpholinopropyl) sulfamoyl) propionic acid
Sap (N36) (R) -2-amino-3- (N- (1, 3-dihydroxypropan-2-yl) sulfamoyl) propionic acid
Sap (N37) (R) -2-amino-3- (N- (4-hydroxy-3- (hydroxymethyl) butyl) sulfamoyl) -propionic acid
Sap (N38) (R) -2-amino-3- (N- (piperidin-4-ylmethyl) sulfamoyl) propionic acid
Sap (N39) (R) -2-amino-3- (N-methyl-N- ((tetrahydro-2H-pyran-4-yl) methyl) -sulfamoyl) propionic acid
Sap (N40) (2R) -2-amino-3- (N-methyl-N- (2- (1-methylpyrrolidin-2-yl) ethyl) -sulfamoyl) propionic acid
Sap (N41) (R) -2-amino-3- (N- (thiazol-2-ylmethyl) sulfamoyl) propionic acid
Sap (N42) (R) -2-amino-3- (N- ((1-methyl-1H-imidazol-4-yl) methyl) sulfamoyl) -propionic acid
Sap (N43) (R) -2-amino-3- (N-benzylsulfamoyl) propionic acid
Sap (N44) (R) -2-amino-3- (N- (4- (methylsulfonyl) benzyl) sulfamoyl) propionic acid
Sap (N45) (R) -2-amino-3- (N- (pyridin-3-ylmethyl) sulfamoyl) propionic acid
Sap (N46) (R) -2-amino-3- (N- (4- (trifluoromethyl) benzyl) sulfamoyl) propionic acid
Sap (N47) (R) -2-amino-3- (N- (2-methoxybenzyl) -N-methylsulfamoyl) propionic acid
Sap (N48) (R) -2-amino-3- (N- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) -sulfamoyl) propionic acid
Sap (N49) (R) -2-amino-3- (N- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) methyl) -sulfamoyl) propionic acid
Sap (N50) (R) -3- (N- (2- (1H-indol-2-yl) ethyl) sulfamoyl) -2-aminopropionic acid
Sap (N51) (R) -2-amino-3- (indolin-1-ylsulfonyl) propionic acid
Sap (N52) (R) -2-amino-3- (5, 6-dihydro-1, 7-naphthyridin-7 (8H) -ylsulfonyl) -propionic acid
Sap (N53) (R) -2-amino-3- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -ylsulfonyl) -propionic acid
Sap (N54) (R) -2-amino-3- (5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -ylsulfonyl) -propionic acid
Sap (N55) (R) -3- (4- (1H-imidazol-1-yl) piperidin-1-ylsulfonyl) -2-aminopropionic acid
Sap (N56) (R) -3- (4- (1H-imidazol-2-yl) piperidin-1-ylsulfonyl) -2-aminopropionic acid
Sap (N57) (R) -3- (1, 4-oxazepin-4-ylsulfonyl) -2-aminopropionic acid
Sap (N58) (R) -2-amino-3- (4-methyl-1, 4-diazepin-1-ylsulfonyl) propionic acid
Sap (N59) (2R) -2-amino-3- (N- (2, 3-dihydro-1H-inden-1-yl) sulfamoyl) propionic acid
Sap (N60) (2R) -2-amino-3- (N- (1,2,3, 4-tetrahydronaphthalen-1-yl) sulfamoyl) -propionic acid
Sap (N61) (R) -2-amino-3- (4- (2-hydroxyethyl) piperazin-1-ylsulfonyl) propionic acid
Dap (SN1) (S) -2-amino-3- (sulfamoylamino) propionic acid
Dap (SN2) (S) -2-amino-3- (N-methylsulfamoylamino) propionic acid
Dap (SN3) (S) -2-amino-3- (N, N-dimethylsulfamoylamino) propionic acid
Dap (SN4) (S) -2-amino-3- (N-isopropylaminosulfonylamino) propionic acid
Dap (SN5) (S) -2-amino-3- (N-cyclopropylsulfamoylamino) propionic acid
Dap (SN6) (S) -2-amino-3- (N-isobutylsulfamoylamino) propionic acid
Dap (SN7) (S) -2-amino-3- (N- (2,2, 2-trifluoroethyl) sulfamoylamino) propionic acid
Dap (SN8) (S) -2-amino-3- (azetidin-1-ylsulfonylamino) propionic acid
Dap (SN9) (S) -2-amino-3- (pyrrolidin-1-ylsulfonylamino) propionic acid
Dap (SN10) (S) -2-amino-3- (piperidin-1-ylsulfonylamino) propionic acid
Dap (SN11) (S) -2-amino-3- (morpholinosulfonylamino) propanoic acid
Dap (SN12) (S) -2-amino-3- (piperazin-1-ylsulfonylamino) propionic acid
Dap (SN13) (S) -2-amino-3- (4-methylpiperazin-1-ylsulfonylamino) propionic acid
Dap (SN14) (S) -3- (4-Acetylpiperazin-1-ylsulfonylamino) -2-aminopropionic acid
Dap (SN15) (S) -2-amino-3- (4-hydroxypiperidin-1-ylsulfonylamino) propionic acid
Dap (SN16) (2S) -2-amino-3- (2-methyl-1-oxo-2, 6-diazaspiro [4.5] decan-6-yl-sulfonylamino) propanoic acid
Dap (SN17) (S) -2-amino-3- (4- (dimethylamino) piperidin-1-ylsulfonylamino) -propionic acid
Dap (SN18) (2S) -2-amino-3- (7-methyl-1, 7-diazaspiro [4.4] nonan-1-ylsulfonylamino) -propionic acid
Dap (SN19) (S) -2-amino-3- (2, 2-dimethylpyrrolidin-1-ylsulfonylamino) propanoic acid
Dap (SN20) (S) -2-amino-3-N-cyclopentylsulfamoylamino) propionic acid
Dap (SN21) (S) -2-amino-3-N-cyclohexylsulfamoylamino) propionic acid
Dap (SN22) (S) -2-amino-3- (N- (tetrahydro-2H-pyran-4-yl) sulfamoylamino) -propionic acid
Dap (SN23) (S) -2-amino-3- (N- (2-hydroxyethyl) sulfamoylamino) propionic acid
Dap (SN24) (S) -2-amino-3- (N- (2-methoxyethyl) sulfamoylamino) propionic acid
Dap (SN25) (S) -2-amino-3- (N- (2-aminoethyl) sulfamoylamino) propionic acid
Dap (SN26) (S) -2-amino-3- (N- (2- (dimethylamino) ethyl) sulfamoylamino) propanoic acid
Dap (SN27) (S) -2-amino-3- (N- (2-methoxyethyl) -N-methylsulfamoylamino) -propionic acid
Dap (SN28) (S) -2-amino-3- (N- (2- (dimethylamino) ethyl) -N-methylsulfamoylamino) -propionic acid
Dap (SN29) (S) -2-amino-3- (N- (3-aminopropyl) sulfamoylamino) propionic acid
Dap (SN30) (S) -2-amino-3- (N- (3- (dimethylamino) propyl) sulfamoylamino) -propionic acid
Dap (SN31) (S) -2-amino-3- (N- (3- (dimethylamino) propyl) -N-methylsulfamoylamino) -propionic acid
Dap (SN32) (S) -3- (N- (2-Acetaminoethyl) sulfamoylamino) -2-aminopropionic acid
Dap (SN33) (S) -2-amino-3- (N- (2- (pyrrolidin-1-yl) ethyl) sulfamoylamino) propionic acid
Dap (SN34) (S) -2-amino-3- (N- (2-morpholinoethyl) sulfamoylamino) propanoic acid
Dap (SN35) (S) -2-amino-3- (N- (3-morpholinopropyl) sulfamoylamino) propanoic acid
Dap (SN36) (S) -2-amino-3- (N- (1, 3-dihydroxypropan-2-yl) sulfamoylamino) -propionic acid
Dap (SN37) (S) -2-amino-3- (N- (4-hydroxy-3- (hydroxymethyl) butyl) sulfamoylamino) -propionic acid
Dap (SN38) (S) -2-amino-3- (N- (piperidin-4-ylmethyl) sulfamoylamino) propionic acid
Dap (SN39) (S) -2-amino-3- (N-methyl-N- ((tetrahydro-2H-pyran-4-yl) methyl) -sulfamoylamino) propionic acid
Dap (SN40) (2S) -2-amino-3- (N-methyl-N- (2- (1-methylpyrrolidin-2-yl) ethyl) -sulfamoylamino) propionic acid
Dap (SN41) (S) -2-amino-3- (N- (thiazol-2-ylmethyl) sulfamoylamino) propionic acid
Dap (SN42) (S) -2-amino-3- (N- ((1-methyl-1H-imidazol-4-yl) methyl) -sulfamoylamino) propionic acid
Dap (SN43) (S) -2-amino-3- (N-benzylsulfamoylamino) propionic acid
Dap (SN44) (S) -2-amino-3- (N- (4- (methylsulfonyl) benzyl) sulfamoylamino) -propionic acid
Dap (SN45) (S) -2-amino-3- (N- (pyridin-3-ylmethyl) sulfamoylamino) propanoic acid
Dap (SN46) (S) -2-amino-3- (N- (4- (trifluoromethyl) benzyl) sulfamoylamino) -propionic acid
Dap (SN47) (S) -2-amino-3- (N- (2-methoxybenzyl) -N-methylsulfamoylamino) -propionic acid
Dap (SN48) (S) -2-amino-3- (N- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) -sulfamoylamino) propanoic acid
Dap (SN49) (S) -2-amino-3- (N- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) methyl) -sulfamoylamino) propionic acid
Dap (SN50) (S) -3- (N- (2- (1H-indol-2-yl) ethyl) sulfamoylamino) -2-aminopropionic acid
Dap (SN51) (S) -2-amino-3- (indolin-1-ylsulfonylamino) propionic acid
Dap (SN52) (S) -2-amino-3- (5,6,7, 8-tetrahydro-1, 7-naphthyridine-7-sulfonamido) -propionic acid
Dap (SN53) (S) -2-amino-3- (1,2,3, 4-tetrahydro-1, 5-naphthyridine-1-sulfonamido) -propionic acid
Dap (SN54) (S) -2-amino-3- (5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine-7-sulfonamido) -propionic acid
Dap (SN55) (S) -3- (4- (1H-imidazol-1-yl) piperidin-1-ylsulfonylamino) -2-amino-propionic acid
Dap (SN56) (S) -3- (4- (1H-imidazol-2-yl) piperidin-1-ylsulfonylamino) -2-amino-propionic acid
Dap (SN57) (S) -3- (1, 4-Oxazepin-4-ylsulfonylamino) -2-aminopropionic acid
Dap (SN58) (S) -2-amino-3- (4-methyl-1, 4-diazepin-1-ylsulfonylamino) propionic acid
Dap (SN59) (2S) -2-amino-3- (N- (2, 3-dihydro-1H-inden-1-ylamino) sulfamoyl) -propionic acid
Dap (SN60) (2S) -2-amino-3- (N- (1,2,3, 4-tetrahydronaphthalen-1-yl) sulfamoylamino) -propionic acid
Dap (SN61) (S) -2-amino-3- (4- (2-hydroxyethyl) piperazine-1-sulfonamido) propanoic acid
Dap (UN1) (S) -2-amino-3-ureidopropionic acid
Dap (UN2) (S) -2-amino-3- (3-methylureido) propionic acid
Dap (UN3) (S) -2-amino-3- (3, 3-dimethylureido) propionic acid
Dap (UN4) (S) -2-amino-3- (3-isopropylureido) propionic acid
Dap (UN5) (S) -2-amino-3- (3-cyclopropylureido) propionic acid
Dap (UN6) (S) -2-amino-3- (3-isobutylureido) propionic acid
Dap (UN7) (S) -2-amino-3- (3- (2,2, 2-trifluoroethyl) ureido) propanoic acid
Dap (UN8) (S) -2-amino-3- (azetidine-1-carboxyamino) propionic acid
Dap (UN9) (S) -2-amino-3- (pyrrolidine-1-carboxyamino) propionic acid
Dap (UN10) (S) -2-amino-3- (piperidine-1-carboxyamino) propionic acid
Dap (UN11) (S) -2-amino-3- (morpholine-4-carboxyamino) propionic acid
Dap (UN12) (S) -2-amino-3- (piperazine-1-carboxyamino) propionic acid
Dap (UN13) (S) -2-amino-3- (4-methylpiperazine-1-carboxyamino) propionic acid
Dap (UN14) (S) -3- (4-acetylpiperazine-1-carboxyamino) -2-aminopropionic acid
Dap (UN15) (S) -2-amino-3- (4-hydroxypiperidine-1-carboxyamino) propionic acid
Dap (UN16) (2S) -2-amino-3- (2-methyl-1-oxo-2, 6-diazaspiro [4.5] decane e-6-carboxyamino) propionic acid
Dap (UN17) (S) -2-amino-3- (4- (dimethylamino) piperidine-1-carboxyamino) -propionic acid
Dap (UN18) (2S) -2-amino-3- (7-methyl-1, 7-diazaspiro [4.4] nonane-1-carboxyamino) -propionic acid
Dap (UN19) (S) -2-amino-3- (2, 2-dimethylpyrrolidine-1-carboxyamino) propionic acid
Dap (UN20) (S) -2-amino-3- (3-cyclopentylureido) propionic acid
Dap (UN21) (S) -2-amino-3- (3-cyclohexylureido) propionic acid
Dap (UN22) (S) -2-amino-3- (3- (tetrahydro-2H-pyran-4-yl) ureido) propanoic acid
Dap (UN23) (S) -2-amino-3- (3- (2-hydroxyethyl) ureido) propanoic acid
Dap (UN24) (S) -2-amino-3- (3- (2-methoxyethyl) ureido) propanoic acid
Dap (UN25) (S) -2-amino-3- (3- (2-aminoethyl) ureido) propanoic acid
Dap (UN26) (S) -2-amino-3- (3- (2- (dimethylamino) ethyl) ureido) propanoic acid
Dap (UN27) (S) -2-amino-3- (3- (2-methoxyethyl) -3-methylureido) propionic acid
Dap (UN28) (S) -2-amino-3- (3- (2- (dimethylamino) ethyl) -3-methylureido) propanoic acid
Dap (UN29) (S) -2-amino-3- (3- (3-aminopropyl) ureido) propanoic acid
Dap (UN30) (S) -2-amino-3- (3- (3- (dimethylamino) propyl) ureido) propanoic acid
Dap (UN31) (S) -2-amino-3- (3- (3- (dimethylamino) propyl) -3-methylureido) -propionic acid
Dap (UN32) (S) -3- (3- (2-acetamido ethyl) ureido) -2-aminopropionic acid
Dap (UN33) (S) -2-amino-3- (3- (2- (pyrrolidin-1-yl) ethyl) ureido) propanoic acid
Dap (UN34) (S) -2-amino-3- (3- (2-morpholinoethyl) ureido) propanoic acid
Dap (UN35) (S) -2-amino-3- (3- (3-morpholinopropyl) ureido) propanoic acid
Dap (UN36) (S) -2-amino-3- (3- (1, 3-dihydroxypropan-2-yl) ureido) propanoic acid
Dap (UN37) (S) -2-amino-3- (3- (4-hydroxy-3- (hydroxymethyl) butyl) ureido) -propionic acid
Dap (UN38) (S) -2-amino-3- (3- (piperidin-4-ylmethyl) ureido) propionic acid
Dap (UN39) (S) -2-amino-3- (3-methyl-3- ((tetrahydro-2H-pyran-4-yl) methyl) ureido) -propionic acid
Dap (UN40) (2S) -2-amino-3- (3-methyl-3- (2- (1-methylpyrrolidin-2-yl) ethyl) ureido) -propionic acid
Dap (UN41) (S) -2-amino-3- (3- (thiazol-2-ylmethyl) ureido) propionic acid
Dap (UN42) (S) -2-amino-3- (3- ((1-methyl-1H-imidazol-4-yl) methyl) ureido) -propionic acid
Dap (UN43) (S) -2-amino-3- (3-benzylureido) propionic acid
Dap (UN44) (S) -2-amino-3- (3- (4- (methylsulfonyl) benzyl) ureido) propanoic acid
Dap (UN45) (S) -2-amino-3- (3- (pyridin-3-ylmethyl) ureido) propionic acid
Dap (UN46) (S) -2-amino-3- (3- (4- (trifluoromethyl) benzyl) ureido) propanoic acid
Dap (UN47) (S) -2-amino-3- (3- (2-methoxybenzyl) -3-methylureido) propionic acid
Dap (UN48) (S) -2-amino-3- (3- ((1-methyl-1H-benzo [ d ] imidazol-2-yl) methyl) ureido) -propionic acid
Dap (UN49) (S) -2-amino-3- (3- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) methyl) -ureido) propanoic acid
Dap (UN50) (S) -3- (3- (2- (1H-indol-2-yl) ethyl) ureido) -2-aminopropionic acid
Dap (UN51) (S) -2-amino-3- (indoline-1-carboxyamino) propionic acid
Dap (UN52) (S) -2-amino-3- (5,6,7, 8-tetrahydro-1, 7-naphthyridine-7-carboxyamino) -propionic acid
Dap (UN53) (S) -2-amino-3- (1,2,3, 4-tetrahydro-1, 5-naphthyridin-1-carboxyamino) -propionic acid
Dap (UN54) (S) -2-amino-3- (5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine-7-carboxyamino) -propionic acid
Dap (UN55) (S) -3- (4- (1H-imidazol-1-yl) piperidine-1-carboxyamino) -2-aminopropionic acid
Dap (UN56) (S) -3- (4- (1H-imidazol-2-yl) piperidine-1-carboxyamino) -2-aminopropionic acid
Dap (UN57) (S) -3- (1, 4-Oxazepin-4-carboxyamino) -2-aminopropionic acid
Dap (UN58) (S) -2-amino-3- (4-methyl-1, 4-diazepine-1-carboxyamino) propionic acid
Dap (UN59) (2S) -2-amino-3- (3- (2, 3-dihydro-1H-inden-1-yl) ureido) propanoic acid
Dap (UN60) (2S) -2-amino-3- (3- (1,2,3, 4-tetrahydronaphthalen-1-yl) ureido) -propionic acid
Dap (UN61) (S) -2-amino-3- (4- (2-hydroxyethyl) piperazine-1-carboxyamino) -propionic acid
Dap (S1) (S) -2-amino-3- (methylsulphonamido) propanoic acid
Dap (S2) (S) -2-amino-3- (ethylsulfonamido) propanoic acid
Dap (S3) (S) -2-amino-3- (1-methylethylsulfonamido) propanoic acid
Dap (S4) (S) -2-amino-3- (cyclopropanesulfonamido) propanoic acid
Dap (S5) (S) -2-amino-3- (2-methylpropylsulfonamido) propionic acid
Dap (S6) (S) -2-amino-3- (2,2, 2-trifluoroethylsulfonamido) propanoic acid
Dap (S7) (S) -2-amino-3- (cyclopentanesulfonamido) propionic acid
Dap (S8) (S) -2-amino-3- (Cyclohexanesulphonamido) propanoic acid
Dap (S9) (S) -2-amino-3- (tetrahydro-2H-pyran-4-sulfonamido) propanoic acid
Dap (S10) (S) -2-amino-3- (phenylsulphonamido) propanoic acid
Dap (S11) (S) -2-amino-3- (4-aminophenylsulfonamido) propanoic acid
Dap (S12) (S) -2-amino-3- (4- (dimethylamino) phenylsulphamido) propanoic acid
Dap (S13) (S) -2-amino-3- (4-morpholinophenylsulphonamido) propanoic acid
Dap (S14) (S) -2-amino-3- (4-cyanophenylsulfonamido) propionic acid
Dap (S15) (S) -2-amino-3- (5-cyanopyridine-2-sulfonamido) propanoic acid
Dap (S16) (S) -2-amino-3- (1H-pyrazole e-4-sulfonamido) propionic acid
Dap (S17) (S) -2-amino-3- (1H-1,2, 4-triazole-5-sulfonamido) propanoic acid
Dap (S18) (S) -2-amino-3- (1, 1-Dimethylethylsulfonamido) propanoic acid
Dap (A1) (S) -3-acetylamino-2-aminopropionic acid
Dap (A2) (S) -2-amino-3-propionamidopropionic acid
Dap (A3) (S) -2-amino-3-isobutyramidopropionic acid
Dap (A4) (S) -2-amino-3- (cyclopropanecarboxamido) propionic acid
Dap (A5) (S) -2-amino-3- (3,3, 3-trifluoropropionamide) propionic acid
Dap (A6) (S) -2-amino-3- (4,4, 4-trifluorobutanamide) propionic acid
Dap (A7) (S) -2-amino-3- (3-aminopropionamide) propionic acid
Dap (A8) (S) -2-amino-3- (4-aminobutanamide) propionic acid
Dap (A9) (S) -2-amino-3- (5-aminopentanamide) propionic acid
Dap (A10) (S) -2-amino-3- (3-methoxypropionamide) propionic acid
Dap (A11) (S) -2-amino-3- (3- (methylamino) propionamide) propionic acid
Dap (A12) (S) -2-amino-3- (3- (dimethylamino) propanamide) propionic acid
Dap (A13) (S) -2-amino-3- (3- (phenylamino) propanamide) propionic acid
Dap (A14) (2S) -2-amino-3- (3-aminobutanamide) propionic acid
Dap (A15) (S) -2-amino-3- (3-amino-3-methylbutyramide) propionic acid
Dap (A16) (S) -2-amino-3- (3- (methylsulfonyl) propanamide) propionic acid
Dap (A17) (S) -2-amino-3- (2-cyclopropylacetamido) propionic acid
Dap (A18) (2S) -2-amino-3- (2- (pyrrolidin-3-yl) acetylamino) propanoic acid
Dap (A19) (2S) -2-amino-3- (2- (pyrrolidin-2-yl) acetylamino) propanoic acid
Dap (A20) (S) -2-amino-3- (2- (piperidin-4-yl) acetylamino) propanoic acid
Dap (A21) (2S) -2-amino-3- (2- (piperidin-3-yl) acetylamino) propanoic acid
Dap (A22) (2S) -2-amino-3- (2- (piperidin-2-yl) acetylamino) propanoic acid
Dap (A23) (S) -2-amino-3- (3- (piperidin-1-yl) propanamide) propionic acid
Dap (A24) (S) -2-amino-3- (3- (piperazin-1-yl) propanamide) propionic acid
Dap (A25) (S) -2-amino-3- (3- (4-methylpiperazin-1-yl) propanamide) propionic acid
Dap (A26) (S) -2-amino-3- (3-morpholinopropionamide) propionic acid
Dap (A27) (S) -2-amino-3- (2- (1-aminocyclohexyl) acetylamino) propanoic acid
Dap (A28) (S) -2-amino-3- (2- (4-aminotetrahydro-2H-pyran-4-yl) acetylamino) -propionic acid
Dap (A29) (2S) -2-amino-3- (2, 2-dimethyl-1, 3-dioxolane-4-carboxyamino) -propionic acid
Dap (A30) (S) -2-amino-3-benzamidopropionic acid
Dap (A31) (S) -2-amino-3- (isonicotinamide) propionic acid
Dap (A32) (S) -2-amino-3- (nicotinamide) propionic acid
Dap (A33) (S) -2-amino-3- (picolinamide) propionic acid
Dap (A34) (S) -2-amino-3- (6- (trifluoromethyl) nicotinamide) propionic acid
Dap (A35) (S) -2-amino-3- (3-methoxybenzamide) propionic acid
Dap (A36) (S) -2-amino-3- (3- (difluoromethoxy) benzamide) propionic acid
Dap (A37) (S) -2-amino-3- (4- (methylsulfonyl) benzamide) propionic acid
Dap (A38) (S) -2-amino-3- (benzo [ d ] [1,3] dioxol-5-carboxyamino) propanoic acid
Dap (A39) (S) -2-amino-3- (2- (pyridin-3-yl) acetamido) propionic acid
Dap (A40) (S) -2-amino-3- (pyrimidine-4-carboxyamino) propionic acid
Dap (A41) (S) -2-amino-3- (3-cyanobenzamide) propionic acid
Dap (A42) (S) -2-amino-3- (thiophene e-2-carboxyamino) propionic acid
Dap (A43) (S) -2-amino-3- (1-methyl-1H-pyrrole-2-carboxyamino) propionic acid
Dap (A44) (S) -2-amino-3- (thiazole-2-carboxyamino) propionic acid
Dap (A45) (S) -2-amino-3- (thiazole-4-carboxyamino) propionic acid
Dap (A46) (S) -2-amino-3- (1-methyl-1H-imidazole e-2-carboxyamino) propionic acid
Dap (A47) (S) -2-amino-3- (1-methyl-1H-imidazole e-5-carboxyamino) propionic acid
Dap (A48) (S) -2-amino-3- (1-methyl-1H-indole-2-carboxyamino) propionic acid
Dap (A49) (S) -2-amino-3- (benzo [ d ] thiazole-2-carboxyamino) propionic acid
Dap (A50) (S) -2-amino-3- (quinoxaline-2-carboxyamino) propionic acid
Dap (A51) (S) -3- (3- (1H-indol-3-yl) propionamide) -2-aminopropionic acid
Dap (A52) (S) -2-amino-3- (2-aminothiazole-4-carboxyamino) propionic acid
Dap (A53) (S) -2-amino-3- (2- (2-aminothiazol-4-yl) acetylamino) propionic acid
Dap (A54) (S) -2-amino-3- (4-guanidinobutanamide) propionic acid
Dap (Suc1) (S) -2-amino-3- (4- (methylamino) -4-oxobutanamide) propanoic acid
Dap (Suc2) (S) -2-amino-3- (4- (dimethylamino) -4-oxobutanamide) propanoic acid
Dap (Suc3) (S) -2-amino-3- (4-morpholino-4-oxobutanamide) propanoic acid
Dap (Suc4) (S) -2-amino-3- (4-oxo-4- (piperazin-1-yl) butanamide) propanoic acid
Dap (Suc5) (S) -2-amino-3- (4- (4-methylpiperazin-1-yl) -4-oxobutanamide) -propionic acid
Dap (Suc6) (S) -2-amino-3- (4- (methylsulfinamido) -4-oxobutanamide) propanoic acid
Dap (Suc7) (S) -2-amino-3- (4- (1, 1-Dimethylethylsulfonamido) -4-oxobutanamide) -propionic acid
Dap (Suc8) (S) -2-amino-3- (4-oxo-4- (phenylsulfinamido) butanamide) propanoic acid
Dap (Suc9) (S) -2-amino-3- (4- (4-chloropyridine-3-sulfonamido) -4-oxobutanamide) -propionic acid
Dap (Suc10) (S) -2-amino-3- (4- (naphthalene-2-sulfonamido) -4-oxobutanamide) -propionic acid
In a preferred embodiment of the invention, the β -hairpin peptidomimetics of general formula (I) are selected from:
cyclo (-Trp-Aib-Trp-Arg-)DPro-Tic-);
Cyclo (-Trp-Aib-Trp-Dab-DPro-Tic-);
Cyclo (-Trp-Cyp-Trp-Arg-)DPro-Tic(7OH)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4S)F)-);
Cyclo (-Trp-Cyp-Trp-Arg-)DPro-Thz-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Thz-);
Cyclo (-Trp (5OH) -Cyp-Trp-Gln-DPro-Thz-);
Cyclo (-Trp (5OH) -Cyp-Trp-Arg-DPro-Tic-);
Cyclo (-2Nal-Cyp-Trp-Gln-DPro-Tic-);
Cyclo (-2Nal-Cyp-Trp-Dab-DPip-Pip-);
Cyclo (-Trp (5OH) -Chx-Trp (5OH) -Arg-DPro-Oic-);
Cyclo (-Trp (5OH) -Cyp-Trp (5OH) -Dap-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab-DPip-Oic-);
Cyclo (-Trp-Cyp-2Nal-Dab-DPip-Oic-);
Cyclo (-Trp-Cyp-2Nal-Gln-DPro-Oic-);
Cyclo (-OctG-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Gln-DPro-Oic-);
Cyclo (-Trp-Chx-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Ac3c-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Ac4c-Trp-Dab-DPro-Oic-);
Ring (A)-Trp-4,4-AC-ThioTHP-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Phe (4F) -Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Tyr (Me) -Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Ala (2Quin) -Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Arg-)DAze-Tic-);
Cyclo (-Trp-Cyp-Trp-Dab-DAze-Tic-);
Cyclo (-Cha-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp (5OH) -Cyp-Trp-Arg-DPro-Thz(5,5Me2)-);
Cyclo (-Trp-Atc-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Ala (2 furyl) -Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Phe (4F) -Ser-DPro-Oic-);
Cyclo (-Trp-Cyp-Phe (4Cl) -Ser-DPro-Oic-);
Cyclo (-Trp-Cyp-Phe (4CF3) -Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-DLTrp (7Aza) -Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Tyr (Ph) -Dab-DPro-Oic-);
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPip-Pro((4R)Ph)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4R)Bn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4R)4BrBn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4R)3CNBn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4S)cHex)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro(5,5Me2)-);
Cyclo (-Trp-Cyp-Phe (4Cl) -Dab-DPro-Hyp(Bn)-);
Cyclo (-Phe (4CN) -Cyp-Phe (4F) -Ser-DPro-Hyp(Bn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(Bn)-);
Cyclo (-Trp-Cyp-Trp-Ser-DPro-Hyp(Bn)-);
Cyclo (-Phe (4CN) -Cyp-Trp-Gln-DPro-Hyp(Bn)-);
Cyclo (-Trp (6Cl) -Cyp-Trp-Dab-DPro-Hyp(Bn)-);
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Hyp(Bn)-);
Cyclo (-Phe (4CN) -Cyp-Trp-Ser-DPip-Hyp(Bn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-(4S)-Hyp(Bn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(Ph)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(4CNBn)-);
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPro-Hyp(4BrBn)-);
Cyclo (-Phe (4CN) -Cyp-Trp-Ser-DPro-Hyp(4BrBn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(4BrBn)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(CONHPh)-);
Cyclo (-Trp-Cyp-Trp-alloThr-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-hArg-)DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-hCys-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Gln (iPr)) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-hSer (Me) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys (Ac) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys (Bz) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys (Me) -one-stepDPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys ((5R) OH) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys (Nic) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Met (O)2)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Ala (Ppz) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dap (CONH)2)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-dab (dab) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-dab (MEMCO) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab (MeO (CH))2)2NHCO)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dap (MeO (CH))2)2)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dap ((MeO (CH))2)2)2)-DPro-Oic-);
Ring (-Ph (4COOMe) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(3CNBn)-);
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Ser-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Ser-DPip-Oic-);
Cyclo (-Trp (6Cl) -Cyp-Trp-Ser-DPro-Oic-);
Cyclo (-Phe (4CN) -Cyp-Trp-Ser-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys (4Oxa) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Ser (Me) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Thr-)DPro-Oic-);
Cyclo (-Bip-Cyp-Trp-Dab-DPro-Oic-);
Loop (-hTyr-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Bbta-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Nle (6OBn) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Tyr (4OHPh) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Tyr (Ph) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Tyr (4MeOCOBN) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Deg-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Ac7c-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Chx (4oxo) -Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Ac8c-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab ((MeO (CH))2)2)(Me)NCO)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-dab (morphCO) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-dab (MePpZCO) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab (MeSO)2)-DPro-Oic-)
Cyclo (-Trp-Cyp-Trp-Dab (4 Me)2NPhSO2)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-dab (Ac) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp-);
Cyclo (-Trp-Cyp-Trp-Dap-DPro-Oic-);
Ring (-Trp-Cyp-Trp-Dab (SN13) -DPro-Oic-);
Or a pharmaceutically acceptable salt thereof.
In a most preferred embodiment of the invention, the β -hairpin peptidomimetics of formula (I) are selected from:
cyclo (-Cha-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPip-Pro((4R)Ph)-);
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro(5,5Me2)-);
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Hyp(Bn)-);
Cyclo (-Trp-Cyp-Trp-Met (O)2)-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dap (CONH)2)-DPro-Oic-);
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Lys (4Oxa) -DPro-Oic-);
Cyclo (-Trp-Cyp-Trp-Dab(MePpzCO)-DPro-Oic-);
Or a pharmaceutically acceptable salt thereof.
In an alternative preferred embodiment of the invention, the β -hairpin peptidomimetics of general formula (I) are selected from:
ring (-Trp-Cyp-Trp-Dab (A55) -DPro-Oic-);
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab(A56)-DPro-Oic-);
Cyclo (-Phe (3 CF)3)-Cyp-Trp-Dab-DPro-Oic-);
Cyclo (-Phe (4 CF)3)-Cyp-Trp-3Pal-DPic-Oic-);
Or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a β -hairpin peptidomimetic of the invention prepared by a method comprising the steps of:
(a) coupling a suitably functionalized solid support to a suitably N-protected derivative of an amino acid at position T as defined above in the desired end product1Or T2Or P1To P4(ii) a Any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;
(b) removing the N-protecting group from the product obtained in step (a);
(c) coupling the product thus obtained to a suitable N-protected derivative of an amino acid which, in the desired end product, is in the position of the next element (T or P), according to the sequence of formula (I) in the counter-clockwise or clockwise direction, in the direction of-COOH to-NH 2; any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;
(d) removing the N-protecting group from the product thus obtained;
(e) repeating steps (c) and (d) until all amino acid residues have been introduced;
(f) if desired, selectively deprotecting one or several of the protected functional groups present in the molecule and chemically converting the reactive groups thus released;
(g) detaching the product thus obtained from the solid support;
(h) cyclizing the product cleaved from the solid support;
(i) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues, and if desired, any protecting groups that may otherwise be present in the molecule; and
(j) if desired, carrying out a further chemical transformation of one or more reactive groups present in the molecule;
(k) if desired, the product thus obtained is converted into a pharmaceutically acceptable salt or a pharmaceutically acceptable or unacceptable salt thus obtained is converted into the corresponding free compound of formula (I) or into a different pharmaceutically acceptable salt.
Advantageously, the methods of the invention can be performed as a parallel array synthesis to generate a library of template-immobilized β -hairpin peptidomimetics of formula (I) above. Such parallel syntheses allow to obtain arrays of numerous compounds of general formula (I), typically 24-192, typically 96, in high yields and with a defined purity, minimizing the formation of dimeric and multimeric by-products. The correct choice of functionalized solid support (i.e., solid support + linker molecule), template and cyclization sites is of great importance.
The functionalized support is conveniently derived from: polystyrene crosslinked with preferably 1-5% divinylbenzene; polystyrene coated with polyethylene glycol spacersAnd polyacrylamide resins (see also Obrecht, D.; Villalgordo, J. -M, "Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compounds", Tetrahedron Organic chemistry series, Vol.17, Pergamon, Elsevier Science, 1998).
The solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule containing at one end an anchoring group for attachment to the solid support and at the other end a selectively cleavable functional group for subsequent chemical conversion and cleavage procedures. For the purposes of the present invention, two types of linkers are used:
type 1 linkers are designed to release the amide group under acidic conditions (Rink H, Tetrahedron Lett.1987,28, 3783-. This type of linker forms an amide with the carboxyl group of the amino acid; examples of resins functionalized by such linker structures include 4- [ ((((2, 4-dimethoxyphenyl) -Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] PS Resin, 4- [ ((((2, 4-dimethoxy-phenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] -4-methylbenzhydrylamine PS Resin (Rink amide MBHA PS Resin), and 4- [ (((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] benzhydrylamine PS Resin (Rink amide BHA PS Resin). Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene, and is functionalized with a 4- (((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) linker.
The type 2 linker is designed to eventually release the carboxyl group under acidic conditions. This type of linker forms acid-labile esters with the carboxyl group of amino acids, typically acid-labile benzyl esters, benzhydryl esters, and trityl esters; examples of such linker substructures include: 2-methoxy-4-hydroxymethylphenoxy: (Linker), 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy (Rink link)Linker), 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid (HMPB linker), trityl, and 2-chlorotrityl. Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene, and is functionalized via a 2-chlorotrityl linker.
When performed as a parallel array synthesis, the process of the invention may advantageously be performed as described below, however, it will be readily apparent to the skilled person how to modify these procedures in the case where it is desired to synthesize a single compound of formula (I) as described above.
25-1000mg, preferably 100mg, of an appropriately functionalized solid support is added to a plurality of reaction tubes, the number of which is equal to the total number of compounds to be synthesized (generally 24-192, generally 96), said solid support preferably being derived from polystyrene crosslinked with 1-3% of divinylbenzene, or from Tentagel resin.
The solvent used must be capable of swelling the resin, including but not limited to: dichloromethane (DCM), Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, Tetrahydrofuran (THF), ethanol (EtOH), Trifluoroethanol (TFE), isopropanol, and the like. Solvent mixtures containing at least one component as a polar solvent (e.g. 20% TFE/DCM,35% THF/NMP) are beneficial for ensuring high reactivity and dissolution of resin-bound peptide chains (Fields, g.b., Fields, c.g., j.am. chem. soc.1991,113, 4202-4207).
With the development of a variety of linkers that release a C-terminal carboxylic acid group under mildly acidic conditions (acid labile groups that do not affect the protection of functional groups in the side chain), significant progress has been made in the synthesis of protected peptide fragments. 2-methoxy-4-hydroxybenzyl alcohol-derived linker: (Linkers, Mergler et al, tetrahedron Lett.1988,294005-4008) can be cleaved by dilute trifluoroacetic acid (0.5-1% TFA in DCM), and during peptide synthesisThe Fmoc deprotection conditions were stable and additional protecting groups based on Boc/tBu were compatible with the protection scheme. Other linkers suitable for the methods of the invention include: super acid-labile 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy linker (Rink linker, Rink, h. tetrahedron lett.1987,28, 3787-one 3790) in which peptide removal requires 10% acetic acid (in DCM) or 0.2% trifluoroacetic acid (in DCM); 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid-derived linker (HMPB-linker,&riniker, Peptides 1991,1990131) which was also cleaved with 1% TFA/DCM to produce peptide fragments containing all acid labile side chain protecting groups; and, in addition, a 2-chlorotrityl chloride linker (Barlos et al, tetrahedron Lett.1989,30, 3943-.
For amino acids and their residues, suitable protecting groups are, for example-for amino groups (as for example, also in the side chain of lysine)
Cbz benzyloxycarbonyl
Boc tert-butoxycarbonyl
Fmoc 9-fluorenylmethoxycarbonyl
Alloc allyloxycarbonyl radical
Teoc trimethylsilyl ethoxycarbonyl
Tc Trichloroethoxycarbonyl
Nps o-nitrophenylsulfonyl
Trt triphenylmethyl or trityl
For carboxyl groups (as are also present, for example, in the side chains of aspartic acid and glutamic acid), by conversion into esters with an alcohol component
tBu tert-butyl
Bn benzyl group
Me methyl group
Ph phenyl
Pac benzoyl
Allyl radical
Tse Trimethylsilylethyl group
Tce Trichloroethyl
For guanidino (as present, for example, in the side chain of arginine)
Pmc 2,2,5,7, 8-pentamethylchromane-6-sulfonyl
Ts tosyl (i.e. p-tosyl)
Cbz benzyloxycarbonyl
Pbf 2,2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl
For hydroxyl groups (as present, for example, in the side chains of threonine and serine)
tBu tert-butyl
Bn benzyl group
Trt trityl radical
For thiol groups (as present in, for example, cysteine side chains)
Acm acetylaminomethyl
tBu tert-butyl
Bn benzyl group
Trt trityl radical
Mtr 4-Methoxytrityl group
The 9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivative is preferably used as a building block for the construction of template-fixed β -hairpin loop mimetics of formula (I). For deprotection, i.e. cleavage of the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF may be used.
The amount of reactants, i.e. amino acid derivatives, is typically 1 to 20 equivalents based on the amount of functionalized solid support initially weighed into the reaction tube (typically 0.1 to 2.85meq/g for polystyrene resins) in milliequivalents/gram (meq/g). Additional equivalents of reactants may be used, if desired, to drive the reaction to completion in a reasonable time. The reaction tubes with the clamping block and manifold were reinserted into the receptacle block and the device was bolted together. Gas flow through the manifold is initiated to provide a controlled environment, e.g., nitrogen, argon, air, etc. The gas stream may also be heated or cooled prior to flowing through the manifold. The heating or cooling of the reaction well is achieved by heating the reaction block or external cooling with propanol/dry ice or the like to achieve the desired synthesis reaction. Agitation is achieved by shaking or magnetic stirring (within the reaction tube). Preferred workstations, however, are, but not limited to, Labsource's Combi-chem workstation and MultiSynTech's-Syro synthesizer.
Activation of the α -carboxyl group is required for the acylation step if the activation is by a commonly used carbodiimide such as dicyclohexylcarbodiimide (DCC, Sheehan)&Hess, J.Am.chem.Soc.1955,77, 1067-1068) or diisopropylcarbodiimide (DIC, Sarantakis et al biochem. Biophys. Res. Commun.1976,73,336-342), then dicyclohexylurea and diisopropylurea, respectively, are insoluble and soluble in the solvents generally used. In a variation of the carbodiimide method, 1-hydroxybenzotriazole (HOBt,&geiger, chem. Ber 1970,103,788-798) as an additive in the coupling mixture. HOBt prevents dehydration, inhibits racemization of activated amino acids, and acts as a catalyst to improve delayed coupling reactions. Some phosphonium reagents have been used as direct coupling agents, such as benzotriazol-1-yl-oxo-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP, Castro et al, Tetrahedron Lett.1975,14, 1219; (Synthesis, 1976,751-Oxazol-1-yl-oxo-tris-pyrrolidine-phosphonium hexafluorophosphate (Py-BOP, Coste et al, Tetra-hydrate Lett.1990,31, 205-; these phosphonium and urea reagents are also suitable for forming HOBt esters in situ with protected amino acid derivatives. More recently, Diphenoxyphosphorylazide (DPPA) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TATU) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino et al, Tetrahedron Lett.1994,35, 2279-.
Since near quantitative coupling reactions are essential, it is desirable to have experimental evidence that the reaction has been completed. Ninhydrin tests (Kaiser et al, anal. biochemistry 1970,34,595) can be easily and quickly performed after each coupling step, wherein a positive colour reaction to an aliquot of the resin-bound peptide qualitatively indicates the presence of a primary amine. Fmoc chemistry allows detection of Fmoc chromophores (when they are released with a base) by spectrophotometry (Meienhofer et al, int.j. peptide Protein res.1979,13, 35-42).
The resin bound intermediates in each reaction tube were washed free of excess retained reactants, solvents and byproducts by repeated exposure to pure solvent.
The washing step is repeated up to 30 times (preferably about 5 times), and the removal efficiency of the reactants, solvents and byproducts is monitored by, for example, TLC, GC, LC-MS or a method of examining the washings.
With each successful conversion, the reaction of the resin bound compound with the reactant in the reaction well described above is repeated, followed by removal of excess reactant, by-product and solvent until the final resin bound fully protected linear peptide is obtained.
Optionally deprotecting the one-peptide prior to detachment of the fully protected linear peptide from the solid support, if desiredOne or several protected functional groups present in the molecule and suitably substituting the reactive groups thus released. For this purpose, the target functional group must first be protected by a protecting group which can be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example of such an amino protecting group which can be selectively removed, for example by Pd ° and phenylsilane (in CH)2Cl2Without affecting the remaining protecting groups present in the molecule, e.g., Fmoc. The reactive groups thus released may then be treated with a reagent suitable for introducing the desired substituent. Thus, for example, an amino group can be acylated by an acylating agent corresponding to the acyl substituent to be introduced.
After detachment of the fully protected peptide from the solid support, the individual solutions/extracts are manipulated as necessary to isolate the final compound. Common operations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization, or additional reactions in solution.
The solution containing the fully protected linear peptide derivative cleaved from the solid support and neutralized with a base is evaporated. The cyclization is then carried out in solution using solvents such as DCM, DMF, dioxane, THF, etc. A variety of the previously mentioned coupling reagents may be used as activators (for amide bond formation) to effect cyclization. The duration of the cyclization is about 6 to 48 hours, preferably about 16 hours. The reaction is followed, for example, by RP-HPLC (reverse phase high performance liquid chromatography). The solvent is then removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a water immiscible solvent such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents to remove any excess coupling agent.
Finally, 95% TFA,2.5% H was used2The fully protected peptide derivative is treated with O,2.5% TIS or other combination of scavengers to effect cleavage of the protecting group. The cleavage reaction time is usually 30 minutes to 12 hours, preferably about 2.5 hours. The volatiles were evaporated to dryness, the crude peptide was dissolved in 20% aqueous AcOH and purified by isopropyl ether or a mixture thereofIt is suitable for solvent extraction herein. The aqueous layer was collected and evaporated to dryness to obtain the fully deprotected cyclic peptide derivative of formula (I) as the final product.
For certain compounds of the invention of general formula (I), additional synthetic steps are required. These transformations may be performed on cyclic or linear peptides that are partially deprotected, attached, or have been released from a solid support, or on the final deprotected molecule, as exemplified below.
Depending on the purity, the peptide derivative can be used directly in the bioassay or subjected to further purification, for example by preparative HPLC.
As mentioned above, the thus obtained fully deprotected product of formula (I) may then be converted into a pharmaceutically acceptable salt, or a pharmaceutically acceptable or unacceptable salt obtained thereby into the corresponding free compound of formula (I), or into a different pharmaceutically acceptable salt, if desired. Any of these operations may be performed by methods well known in the art.
In general, the building blocks for the peptidomimetics of the invention can be synthesized according to methods known in the literature (examples are described below), methods known to those skilled in the art or commercially available. Some additional novel syntheses were performed for the invention, as described in the examples. All other corresponding amino acids have been described as unprotected or Boc-or Fmoc-protected racemates, (D) -or (L) -isomers. It will be appreciated that the unprotected amino acid building blocks can be readily converted to the corresponding desired Fmoc-protected amino acid building blocks of the invention by standard protecting group manipulations. A review describing the general method of synthesizing alpha-amino acids includes: R.Duthraler, tetrahedron (report)1994,349,1540-1650, R.M.Williams, "Synthesis of optional active α -amino acids", tetrahedron organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989. Particularly useful methods for synthesizing optically active, related alpha-amino acids of the invention include: kinetic resolution using hydrolytic enzymes (M.A. Verhovskaya, I.A. Yamskov, Russian chem.Rev.1991,60,1163-1179; R.M. Williams, "Synthesis of optically active alpha-aminoacids", Tetrahedron organic chemistry Series, Vol.7, J.E. Baldwin, P.D. Magnus (Eds.), Pergamon Press, Oxford1989, Chapter7, p.257-279). Kinetic resolution using hydrolytic enzymes includes hydrolysis of amides and nitriles by aminopeptidases or nitrilases, cleavage of N-acyl groups by acylases, and hydrolysis of esters by lipases or proteases. It has been demonstrated that certain enzymes will lead to the specific production of the pure (L) -enantiomer, while others will produce the corresponding (D) -enantiomer (e.g., R.Duthaler, Tetrahedron Report 1994,349,1540-1650; R.M.Williams, "Synthesis of optical active. alpha. -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989).
The beta-hairpin peptidomimetics of the invention are useful in a variety of applications to antagonize CCR10 receptor activity to produce a desired therapeutic effect in humans and other mammals due to their similar etiologies. In particular, they are useful as agents for the treatment and/or prevention of diseases or conditions associated with immune responses in the following fields: inflammation, skin disorders, or cancer, such as, but not limited to: psoriasis, atopic dermatitis, contact allergies and allergic dermatitis, Stevens-Johnson syndrome, bullous skin disease, systemic lupus erythematosus, systemic and multiple sclerosis, allergic asthma, arthritis, graft-versus-host disease, certain melanomas and cutaneous lymphomas, thyroiditis, and inflammatory processes of the gastrointestinal tract and the eye.
For use as a medicament, the β -hairpin peptidomimetics of the invention may be administered alone, as a mixture of several β -hairpin peptidomimetics of the invention, or in combination with other pharmaceutically active agents. The β -hairpin peptidomimetics of the invention may be administered alone or in a pharmaceutical formulation, for example formulated as a suitable formulation with carriers, diluents or excipients well known in the art.
Pharmaceutical compositions comprising the beta-hairpin peptidomimetics of the invention may be prepared by conventional mixing, dissolving, granulating, preparing coated tablets, grinding, emulsifying, encapsulating or lyophilizing. The pharmaceutical compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, diluents, excipients or adjuvants which facilitate the processing of the active β -hairpin peptidomimetics into pharmaceutically acceptable formulations. The appropriate agent depends on the chosen method of administration.
For topical application, the β -hairpin peptidomimetics of the invention may be formulated as solutions, gels, pastes, creams, suspensions, and the like, as is well known in the art.
Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathoracic or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
For injection, the β -hairpin peptidomimetics of the invention may be formulated in a suitable solution, preferably a physiologically compatible buffer, such as Hink solution, Ringer solution or physiological saline buffer. The solution may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β -hairpin peptidomimetics of the invention may be in powder form for admixture with a suitable medium, e.g., sterile pyrogen-free water, prior to use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated, as known in the art, are used in the formulation.
For oral administration, the compounds of the invention can be readily prepared: by mixing the active β -hairpin peptidomimetics with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the β -hairpin peptidomimetics of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient to be treated. For oral formulations, e.g., powders, capsules, and tablets, suitable excipients include: fillers such as lactose, sucrose, mannitol, and sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating; and a binder. If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. If desired, the solid dosage form may be sugar coated or enteric coated, using standard techniques.
For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols and the like. In addition, flavoring agent, antiseptic, colorant, etc. can be added.
For buccal administration, the compositions may take the form of tablets, lozenges, and the like, formulated as conventional.
For administration by inhalation, the β -hairpin peptidomimetics of the invention are conveniently administered from a pressurized pack or an aerosol of a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a mixture of the beta-hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch.
The compounds may also be formulated in rectal or vaginal compositions, for example as solutions for enemas, or as suppositories with suitable suppository bases such as cocoa butter or other glycerides.
In addition to the above formulations, the β -hairpin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the preparation of such depot formulations, the β -hairpin peptidomimetics of the invention may be formulated with a suitable polymeric or hydrophobic material (e.g., an emulsion in a suitable oil) or ion exchange resin, or as a sparingly soluble salt.
In addition, other pharmaceutical delivery systems may be used, such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethyl sulfoxide may also be used. In addition, the β -hairpin peptidomimetics of the invention can be delivered using a slow release system, such as a semipermeable matrix of a solid polymer containing the therapeutic agent. A variety of sustained release materials have been established and are well known to those skilled in the art. Sustained release capsules can release compounds over a period of weeks up to 3 years or more, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic agent, additional protein stabilization strategies may be applied.
Since the β -hairpin peptidomimetics of the present invention may contain charged residues, they may be contained in any of the above-mentioned preparations either in the original form or as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts tend to be more soluble in water and other protic solvents than the corresponding free base forms.
In addition, the compounds of the present invention and their pharmaceutically acceptable salts may be used alone or in solid forms of different forms in any suitable formulation, which may or may not contain varying amounts of solvents, such as hydrates remaining from the crystallization process.
The beta-hairpin peptidomimetics of the invention or compositions thereof can generally be used in amounts effective to achieve the intended purpose. It is to be understood that the amount used will depend on the particular application.
For use in treating or preventing diseases or disorders associated with an etiology involving increased activity of a CCR10 receptor and its ligands (e.g., CCL27 or CCL28), the β -hairpin peptidomimetics of the invention or compositions thereof are administered or applied in a therapeutically effective amount. Determining a therapeutically effective amount is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein.
The effective dose of the active ingredient will vary depending upon the particular compound or pharmaceutical formulation employed, the mode of administration, and the severity and type of the condition being treated. Thus, the dosage regimen is selected based on factors including: routes of administration and clearance, e.g., renal and hepatic function of the patient. A physician, clinician or veterinarian in the art can readily determine and prescribe the amounts of the single active ingredients required to prevent, ameliorate or prevent the disease or its progression. The accuracy of optimization to achieve concentration of the active ingredient without toxicity requires kinetics based on the availability of the active ingredient to the target site. This involves taking into account the distribution, equilibrium and elimination of the active ingredients.
In the case of topical administration or selective uptake, the effective local concentration of the β -hairpin peptidomimetics of the invention may not correlate with plasma concentrations. One skilled in the art would be able to optimize therapeutically effective topical dosages without undue effort.
The invention will now be further described by the following examples, which are intended to be illustrative only and should not be construed as limiting the scope of the invention in any way.
The following abbreviations are used in these examples:
boc tert-butoxycarbonyl;
DCHA dicyclohexylamine;
DEAD diethyl azodicarboxylic acid;
DIPEA diisopropylethylamine;
fmoc fluorenylmethoxycarbonyl;
HATU O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HBTU O- (benzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate;
HCTU O- (6-chlorobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
(benzotriazol-1-yloxy) trispyrrolidinophosphonium hexafluorophosphate;
TIS triisopropylsilane;
TPP triphenylphosphine;
rt Room temperature
Examples
1. Peptide synthesis
1.1 general synthetic procedure
Two general methods, method a and method B, for synthesizing the peptidomimetics of the present invention are exemplified herein. This is done to illustrate the principles and concepts of the invention and is not intended to limit or restrict the invention in any way. One skilled in the art can readily vary these steps, particularly, without limitation, selecting different starting positions within the ring system, and still achieve the preparation of the claimed cyclic peptidomimetic compounds of the present invention.
Coupling of the first protected amino acid residue to the resin
The method A comprises the following steps:
0.5g of 2-chlorotrityl chloride resin (Barlos et al Tetrahedron Lett.1989,30, 3943-. Suspending the resin in CH2Cl2(2.5ml) and allowed to swell at room temperature for 30 minutes. The resin was treated with 0.43mmol (0.6eq) of the first appropriately protected amino acid residue or building block (see below) and in CH2Cl2Mu.l (4eq) of Diisopropylethylamine (DIPEA) in 488. mu.l (2.5ml) was treated and the mixture was shaken at room temperature for 4 hours. Using the resin with CH2Cl2(1x)、DMF(1x)、CH2Cl2(1x), DMF (1x) and CH2Cl2(2x) washing. The resin is added in 30mlCH2Cl2Shaking for 30 min in/MeOH/DIPEA (17:2: 1); then using CH in the following order2Cl2(1x)、DMF(1x)、CH2Cl2(1x)、MeOH(1x)、CH2Cl2(1x)、MeOH(1x)、CH2Cl2(2x)、Et2Washed with O (2 ×) and dried under vacuum for 6 hours.
The method B comprises the following steps:
in a dry flask, 2-chlorotrityl chloride resin (loading: 1.4mmol/g) was added to dry CH2Cl2Middle swelling for 30 min (7ml CH)2Cl2Per gram of resin). 0.8 equivalent of Fmoc-AA-OH and 6 equivalents of DIPEA in dry CH were added2Cl2Solution in DMF (4/1) (10ml/g resin). After 2-4 hours shaking at room temperature, the resin was filtered and successively treated with CH2Cl2、DMF、CH2Cl2DMF and CH2Cl2And (6) washing. Then dry CH is added2Cl2A solution of/MeOH/DIPEA (17:2:1) (10ml/g resin). After shaking for 3 × 30 min, the resin was filtered in a pre-weighed sinter funnel and successively with CH2Cl2、DMF、CH2Cl2、MeOH、CH2Cl2、MeOH、CH2Cl2(2x) and Et2O (2x) wash. The resin was dried under high vacuum overnight. The final mass of the resin was calculated before the quality control.
The following pre-loaded resins were prepared: Fmoc-Tic-2-chlorotrityl resin, Fmoc-Oic-2-chlorotrityl resin, Fmoc-DPro-2-chlorotrityl resin, Fmoc-Arg-2-chlorotrityl resin, Fmoc-DAze-2-chlorotrityl resin, Fmoc-Trp-2-chlorotrityl resin, Fmoc-Hyp (Bn) -2-chlorotrityl resin, Fmoc- (4S) -Hyp (Bn) -2-chlorotrityl resin, Hyp (4BrBn) -2-chlorotrityl resin, Fmoc-Dab-2-chlorotrityl resin, Fmoc-Thz-2-chlorotrityl resin, Fmoc-Pip-2-chlorotrityl resin, Fmoc-Phe (4CN) -2-chlorotrityl resin, Fmoc-Pro ((4R) Ph) -2-chlorotrityl resin, Fmoc-DLAtc-2-Chlorotriphenylmethyl resin, Fmoc-Bbta-2-Chlorotriphenylmethyl resin and Fmoc-DLTrp (7Aza) -2-chlorotrityl resin.
Synthesis of fully protected peptide fragments
The synthesis was carried out in a Syro-peptide synthesizer (MultiSynTech GmbH) using 24-96 reaction vessels. Approximately 60mg (method A) or 80mg (method B) of the above resin (weight of resin before loading) was placed in each vessel. The following reaction cycles were programmed and performed:
the method A comprises the following steps:
steps 3-6 are repeated to add each amino acid residue.
The method B comprises the following steps:
steps 3-6 are repeated to add each amino acid residue.
After the synthesis of the fully protected peptide fragment is terminated, the final compound is prepared using the cleavage, cyclization and building procedures described below.
Cleavage, backbone cyclization and deprotection of peptides
After assembly of the linear peptide, the resin was suspended in 1ml of CH2Cl21% TFA (v/v; 0.14mmol) in (1) for 3 minutes and filtered, and the filtrate is taken up with 1ml of aqueous solution in CH2Cl220% DIPEA (v/v; 1.15mmol) in (D) was neutralized. This step was repeated four times to ensure complete cutting. The resin was diluted with 1ml of CH2Cl2Washed three times. Will contain the CH of the product2Cl2The layer was evaporated to dryness.
The fully protected linear peptide was dissolved in 8ml of dry DMF. The peptide was then added to 2 equivalents of HATU in dry DMF (1-2ml) and 4 equivalents of DIPEA in dry DMF (1-2ml) and stirred for 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7ml of CH2Cl2Neutralized and extracted three times with 4.5ml of 10% acetonitrile in water (v/v). Will CH2Cl2The layer was evaporated to dryness.
To completely deprotect the peptide4-7ml of the cleavage mixture TFA/TIS/H were added2O (95:2.5:2.5) and the mixture is kept at room temperature for 2.5-4 hours until the reaction is complete. The reaction mixture was evaporated to dryness and the crude peptide was dissolved in 7ml of 20% AcOH (v/v) in water and extracted three times with 4ml of diisopropyl ether. The aqueous layers were collected and evaporated to dryness and the residue was purified by preparative reverse phase LC-MS.
Purification procedure (preparative reverse phase LC-MS)
The compounds were purified by reverse phase chromatography using a Vydac 218MS column, 30x 150mm (Cat No.218MS103015), 10 μm or Waters XBridge C18, 30x 150mm, 5 μm (Cat No. 186002982).
The mobile phases used were:
a: 0.1% TFA v/v in Water/acetonitrile 95/5
B: 0.1% TFA in acetonitrile
The gradient slope during preparation was corrected each time based on LC-MS analysis of the crude product. For example, a typical run (purification of example 94) was run at a flow rate of 35ml/min over a gradient of 0-2 min 0% B, 9 min 55% B to a final 9.1-12.5 min 100% B (delay time: 7.38 min in this case).
And (3) detection: MS and UV @220nm
The collected fractions were evaporated using a Genevac HT4 evaporator or a Buchi system.
Alternatively, for larger amounts, the following LC-purification system was used:
column: vydac 218MS, 10 μm, 50X 150mm
Mobile phase A: 0.1% TFA in Water
A mobile phase B: 0.1% TFA in acetonitrile
Flow rate: 150ml/min
And (3) detection: UV @220nm
After lyophilization, the product is typically obtained as a white to off-white powder and analyzed by the following HPLC-ESI-MS method. Analytical data after preparative HPLC purification are shown in table 1.
1.2 analytical methods
Analytical method A:
analytical HPLC delay time (RT in minutes) was determined using a Gemini NX column, 50X2.0mm, (cod.00B-4453-B0-Phenomenex) with the following solvent A (H)2O +0.1% TFA) and B (CH)3CN +0.1% TFA) and gradient determination: 0-0.1 min: 97% A, 3% B; 2.7 minutes: 3% A97% B; 2.7-3 minutes: 3% a, 97% B; 3.05-3.3 min: 97% A, 3% B. Flow rate =0.8ml/min
Analysis method B:
analytical HPLC delay time (RT in minutes) Using an Xbridge C18 column, 50X2.0mm, (cod.186003084-Waters) with the following solvent A (H)2O +0.1% TFA) and B (CH)3CN +0.1% TFA) and gradient determination: 0-0.05 min: 97% A, 3% B; 3 minutes: 3% A97% B; 3-3.6 min: 3% a, 97% B; 3.6-4.3 minutes: 97% A, 3% B. Flow rate =0.5ml/min
Analysis method C:
analytical HPLC delay time (RT in minutes) Using a UPLC BEH C18 column, 100X 2.1mm, (cod.186002352-Waters) with the following solvent A (H)2O +0.1% TFA) and B (CH)3CN +0.1% TFA) and gradient determination: 0-0.2 min: 99% A, 1% B; 4 minutes: 35% a 65% B; 4.05-4.2 min: 5% A, 95% B; 4.2-4.5 min: 99% A, 1% B. Flow rate =0.6ml/min
Analysis method D:
analytical HPLC delay time (RT in min) Using an HPLC Agilent HP1100 Ascentisoxpress C18 column, 50X 3mm, (cod.53811-U-Supelco) with the following solvents A (H2O +0.1% TFA) and B (CH 2O +0.1% TFA)3CN +0.1% TFA) and gradient determination: 0-0.05 min: 97% A, 3% B; 3.35 minutes: 67% A, 33% B; 3.4-3.65 minutes: 3% a, 97% B; 3.67-3.7 minutes: 97% A, 3% B. Flow rate =1.3ml/min
1.3 Synthesis of Special building blocks
(2S,4R) -4- (4-Cyanobenzyloxy) -1- (tert-Butoxycarbonyl) pyrrolidine-2-carboxylic acid
(2S,4R) -1- (tert-butoxycarbonyl) -4-hydroxypyrrolidine-2-carboxylic acid (1.0 g; 4.3mmol) in dry THF (5ml) was carefully combined at 0 ℃ with a suspension of sodium hydride (60% in paraffin oil, total 420 mg; 5.2 mmol; 2.4eq) in dry THF (9 ml). The mixture was stirred at 0 ℃ and then a solution of 4- (bromomethyl) benzonitrile (1.5 g; 7.8 mmol; 1.8eq) in dry THF (5ml) was added in portions. The mixture was then stirred at 0 ℃ for 45 minutes and at room temperature until the reaction progress was complete. The crude reaction mixture was diluted with 5% aqueous citric acid (50ml) and extracted twice with ethyl acetate and MgSO4Dried and concentrated in vacuo to yield 3.2g of crude product.
Flash chromatography on silica gel (CH)2Cl2MeOH 98:2-9:1) gave 580mg of (2S,4R) -4- (4-cyanophenylmethoxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid.
(2S,4R) -4- (4-cyanophenylmethyloxy) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (250mg, 722. mu. mol) was dissolved in 4M HCl in dioxane (3ml, 12mmol), and the solution was stirred at room temperature for 1 hour. The product was concentrated and Et2And O washing. A clear solution was obtained by adding 120mg of potassium carbonate (866. mu. mol) to the residue suspended in 5ml of water and 15ml of acetonitrile. N-succinimidyl carbonate 9-fluorenylmethyl ester (292mg, 866. mu. mol) was added stepwise to the solution at 0 ℃. The reaction mixture was stirred at room temperature overnight, diluted in water and Et2O (pH about 9-10) treatment was performed twice. The organic layer was washed with NaHCO3The saturated aqueous solutions were washed twice and they were combined, acidified to pH =1-2 with 5N HCl and extracted twice more with EtOAc. All combined layers were dried (MgSO)4) And concentrating to obtain229mg of (2S,4R) -4- (4-cyanophenylmethyloxy) -1- (((9H-fluoren-9-yl) methoxy) carbonyl) pyrrolidine-2-carboxylic acid.
(S) -2- (((9H-fluoren-9-yl) methoxy) carbonylamino) -3- (4- (4- (methoxycarbonyl) -phenylmethyloxy) phenyl) propanoic acid
(S) -tert-butyl 2- (((9H-fluoren-9-yl) methoxy) carbonylamino) -3- (4-hydroxyphenyl) propanoate (100mg, 218. mu. mol), triphenylphosphine (TPP, 171mg, 653. mu. mol) and methyl 4- (hydroxymethyl) benzoate (80mg, 479. mu. mol) were combined in 4ml of dry benzene under nitrogen. A solution of DEAD (40% in toluene, 299. mu.l, 653. mu. mol) diluted with 3ml of dry benzene was added dropwise at 4 ℃ over 20 minutes. The mixture was stirred at 4 ℃ for 20 minutes and then at room temperature overnight. The addition of TPP (57mg, 218. mu. mol) and DEAD (100. mu.l, 218. mu. mol) was repeated twice to drive the reaction to completion. The volatiles were removed in vacuo and the crude material was purified by flash chromatography on silica gel (hexane/ethyl acetate 95/5-1/1) to yield 60mg of (S) -tert-butyl 2- (Fmoc-amino) - ((4-methoxycarbonyl) benzyl) tyrosine.
The purified tert-butyl-tyrosine derivative (55mg, 91. mu. mol) was dissolved in 600. mu.l dichloromethane and cooled to 0 ℃. 600 μ l TFA was added slowly and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed and co-evaporated with dichloromethane 1 time and toluene 3 times to yield 46mg of the final building block (S) -2- (((9H-fluoren-9-yl) methoxy) carbonyl-amino) -3- (4- (4- (methoxycarbonyl) -phenylmethyloxy) phenyl) propanoic acid.
1.4 Synthesis of peptide sequences
Examples 1,2 and 9 are shown in table 1.
Peptides were synthesized according to general procedure A, starting with amino acid (S) -1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid grafted onto a resin (Fmoc-Tic-2-chlorotrityl resin). Straight chain peptides inThe solid support was synthesized according to the above procedure in the following order: resin-Tic-DPro-P4-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see examples 1,2, 9 in table 1.
Examples 3 and 8 are shown in table 1.
The peptide was synthesized according to general procedure A, starting with the amino acid L-arginine grafted onto a resin (Fmoc-Arg-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Arg-Trp-Cyp-P1-T2-T1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see examples 3, 8 in table 1.
Examples 4-6 are shown in Table 1.
The peptides were synthesized according to general method A for grafting onto a resin (Fmoc-DPro-2-chlorotrityl resin) of the amino acid D-proline. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-DPro-P4-P3-P2-P1-T2. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see examples 4,5, 6 in table 1.
Example 7 is shown in table 1.
Peptido rootThe synthesis was according to general procedure A, starting with the amino acid (S) -thiazolidine-4-carboxylic acid grafted onto a resin (Fmoc-Thz-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Thz-DPro-Gln-Trp-Cyp-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 7 in table 1.
Example 10 is shown in table 1.
The peptide was synthesized according to general procedure a, starting with the amino acid L-piperidinecarboxylic acid grafted to a resin (Fmoc-Pip-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Pip-DPip-Dab-Trp-Cyp-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 10 in table 1.
Examples 11-24 and 104 are shown in Table 1.
The peptide was synthesized according to general procedure a, starting with amino acid (S) - (2S, 3aS, 7aS) -1-octahydro-1H-indole-2-carboxylic acid grafted onto a resin (Fmoc-Oic-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Oic-T1-P4-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see examples 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 104 in table 1.
Examples 25 and 26 are shown in table 1.
The peptides were synthesized according to general method A for grafting onto a resin (Fmoc-DAze-2-chlorotrityl resin) of the amino acid D-azetidine-2-carboxylic acid. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-DAze-P4-P3-P2-P1-T2-. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder, characterized by HPLC-MS for example 25, analytical method a, and analytical method C for example 26, as described above. For analytical data see examples 25, 26 in table 1.
Examples 27 and 28 are shown in table 1.
The peptide was synthesized according to general procedure a, starting with amino acid (S) - (2S, 3aS, 7aS) -1-octahydro-1H-indole-2-carboxylic acid grafted onto a resin (Fmoc-Oic-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Oic-DPro-Dab-Trp-Cyp-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method C as described above. For analytical data see examples 27, 28 in table 1.
Example 29 shown in table 1.
The peptides were synthesized according to general method A for grafting onto a resin (Fmoc-DPro-2-chlorotrityl resin) of the amino acid D-proline. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-DPro-Arg-Trp-Cyp-P1-T2. The product is cleaved from the resin, cyclized, deprotected and passed through the preparative reverse phase as described aboveAnd (5) LC-MS purification.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 29 in table 1.
Example 30 is shown in table 1.
The peptides were synthesized according to general method A for grafting onto a resin (Fmoc-DLAtc-2-chlorotrityl resin) of amino acid (R, S) -2-amino-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-DLAtc-Trp-Oic-DPro-Dab-Trp. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method C as described above. For analytical data see example 30 in table 1.
Example 31 shown in table 1.
The peptide was synthesized according to general procedure B, starting with amino acid (S) - (2S, 3aS, 7aS) -1-octahydro-1H-indole-2-carboxylic acid grafted onto a resin (Fmoc-Oic-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Oic-DPro-Dab-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method B as described above. For analytical data see example 31 in table 1.
Examples 32 to 34, 36, 58 to 70, 76, 79 to 87, 89 to 96, 107, 109 and 110 are shown in Table 1.
The peptide was synthesized according to general procedure B, starting with amino acid (S) - (2S, 3aS, 7aS) -1-octahydro-1H-indole-2-carboxylic acid grafted onto a resin (Fmoc-Oic-2-chlorotrityl resin).The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Oic-T1-P4-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
For example 76, at P1Saponification occurs in the side chain. Thus, esterification with MeOH was performed using standard synthetic procedures prior to purification.
After lyophilization, the product was obtained as a white to off-white powder and characterized by HPLC-MS, analytical methods a or D as described above, and is shown in table 1. For analytical data see examples 32, 33, 34, 36, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 107, 109, 110 in table 1.
Example 35 is shown in table 1.
The peptides were synthesized according to general method A for grafting onto a resin (Fmoc-DLTrp (7Aza) -2-Chlorotriphenylmethyl resin) amino acid 2-amino-3- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) propionic acid. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-DLTrp(7Aza)-Cyp-Trp-Oic-DPro-Dab. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 35 in table 1.
Example 37 shown in table 1.
Peptides were synthesized according to general procedure B, starting with the amino acid 4R-phenyl-L-proline grafted to a resin (Fmoc-Pro ((4R) Ph) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Pro ((4R) Ph) -DPip-Dab-Trp-Cyp-P1. The product is prepared fromResin cleavage, cyclization, deprotection and purification by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 37 in table 1.
Examples 38 to 42, 52 to 53 and 57 shown in Table 1.
The peptides were synthesized according to general method B for grafting onto a resin (Fmoc-DPro-2-chlorotrityl resin) of the amino acid D-proline. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-DPro-Dab-Trp-Cyp-P1-T2. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see examples 38, 39, 40, 41, 42, 52, 53, 57 in table 1.
Examples 43 to 50 shown in Table 1.
The peptide was synthesized according to general procedure B, starting with the amino acid (2S,4R) -4-benzyloxypyrrolidine-2-carboxylic acid grafted to a resin (Fmoc-hyp (bn) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Hyp (Bn) -T1-P4-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see examples 43, 44, 45, 46, 47, 48, 49, 50 in table 1.
Example 51 is shown in table 1.
The peptide was synthesized according to general method B for grafting onto a resin (Fmoc- (4)S) -Hyp (Bn) -2-chlorotrityl resin) of amino acid (2S, 4S) -4-benzyloxypyrrolidine-2-carboxylic acid. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Hyp (Bn) -T1-P4-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 51 in table 1.
Examples 54-56 are shown in Table 1.
Peptides were synthesized according to general procedure B, starting with the amino acid (2S,4R) -4- (4-bromophenylmethyl) -pyrrolidine-2-carboxylic acid grafted to a resin (Fmoc-Hyp (4BrBn) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Hyp (4BrBn) -DPro-P4-P3-P2-P1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above.
For analytical data see examples 54, 55, 56 in table 1.
Example 78 is shown in Table 1.
The peptide was synthesized according to general procedure a, starting with the amino acid (2S) -3- (4-cyanophenyl) -2-amino) propionic acid grafted onto a resin (Fmoc-Phe (4CN) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Phe (4CN) -Oic-DPro-Dab-Trp-Cyp. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 78 in table 1.
Example 88 is shown in table 1.
The peptide was synthesized according to general procedure a, starting with the amino acid (2S) -3- (1-benzothiophen-3-yl) -2-aminopropionic acid grafted onto a resin (Fmoc-Bbta-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Bbta-Oic-DPro-Dab-Trp-Cyp. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 88 in table 1.
Example 103 is shown in table 1.
The peptide was synthesized according to general procedure a, starting with the amino acid (S) -2, 4-diaminobutyric acid grafted onto a resin (Fmoc-Dab-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Dab-Trp-Cyp-Trp-T2-T1. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
After lyophilization, the product was obtained as a white powder and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 103 in table 1.
1.5 subsequent peptide sequence modification
Examples 74 and 75 as shown in table 1.
To a solution of 40mg of example 104 (44. mu. mol) in 0.5ml of dry DMF was added 4mg of sodium hydride (55% in mineral oil, 87. mu. mol) at 0 ℃. The suspension was stirred for 10 min at 0 ℃ and then sodium iodide (3.3mg, 22. mu. mol) and 2-bromoethyl methyl ether (6. mu.l, 66. mu. mol) were added. The reaction mixture was stirred at room temperature overnight. To complete the reaction, the above addition sequence was repeated and included an additional 9mg of sodium hydride and 20. mu.l of 2-bromoethyl methyl ether. A few drops of water were then added, the reaction mixture was concentrated and purified by preparative reverse phase LC-MS as described above. After lyophilization, 1.7mg of example 74 and 1.8mg of example 75 were obtained as off-white powders and characterized by HPLC-MS, analytical method A as described above.
For analytical data see example 74 and example 75 in table 1.
As in example 73 shown in table 1.
To a solution of 15mg of example 28 (18. mu. mol) and 9. mu.l of DIPEA (54. mu. mol) in 0.5ml of dry THF were added 8mg of ofN-succinimidyl-N- (2-methoxyethyl) carbamate (36. mu. mol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by preparative reverse phase LC-MS as described above. After lyophilization, 2mg of example 73 was obtained and characterized by HPLC-MS, analytical method A as described above.
For analytical data see example 73 in table 1.
As in example 71 shown in table 1.
A solution of 20mg of example 28 (24. mu. mol), 36mg of Boc-dab (Boc) -OH. DCHA (72. mu. mol), 38mg of PyBOP (72. mu. mol) and 25. mu.l of DIPEA (144. mu. mol) in 0.5ml of dry DMF was stirred at room temperature overnight. The reaction mixture was concentrated in CH2Cl2Re-suspended, washed with water and re-concentrated. The crude material was dissolved in 3ml TFA containing 0.1 waterIn (1). After 2 hours the solution was concentrated at room temperature and then passed through preparative reverse phase LC-MS as described above. 2.5mg of example 71 were obtained after lyophilization and characterized by HPLC-MS, analytical method A as described above.
For analytical data see example 71 in table 1.
As in example 72 shown in table 1.
To a solution of 42mg of example 28 (50. mu. mol) and 26. mu.l of DIPEA (150. mu. mol) in 1ml of dry DMF were added 14mg of 2- (2-methoxyethoxy) acetic acid (100. mu. mol) and 53mg of PyBOP (100. mu. mol). The reaction mixture was stirred at room temperature for 1 hour, concentrated, and purified by preparative reverse phase LC-MS as described above. 7mg of example 72 was obtained after lyophilization and characterized by HPLC-MS, analytical method A as described above.
For analytical data see example 72 in table 1.
As in example 108 shown in table 1.
To a solution of 59mg of example 107 (61. mu. mol) and 41. mu.l of DIPEA (242. mu. mol) in 1.2ml of dry DMF were added 19mg of 3- (1-methyl-1H-imidazol-5-yl) propionic acid (121. mu. mol) and 63mg of PyBOP (121. mu. mol). The reaction mixture was stirred at room temperature for 1 hour, concentrated, and purified by preparative reverse phase LC-MS as described above. 30mg of example 108 was obtained after lyophilization and characterized by HPLC-MS, analytical method D as described above.
For analytical data see example 108 in table 1.
As in example 100 shown in table 1.
To 25mg of example 28 (free base; 28. mu. mol) and 19. mu.l of DIPEA (112. mu. mol) in 1ml of dry THF/CHCl3/CH2Cl2To the solution in (1:1:2) was added 6.5. mu.l of methanesulfonyl chloride (84. mu. mol) and a catalytic amount of DMAP, and the reaction mixture was stirred at room temperature overnight. Then an additional 6.5. mu.l of methanesulfonyl chloride (84. mu. mol) and 19. mu.l of DIPEA (112. mu. mol) were added, stirred at room temperature for 4 hours, finally concentrated and purified by preparative reverse phase LC-MS as described above. After lyophilization, 3mg of example 100 was obtained and characterized by HPLC-MS, analytical method A as described above.
For analytical data see example 100 in table 1.
As in example 101 shown in table 1.
Similar to the procedure of example 100, but using 2X 18.5. mu.l of 4- (dimethylamino) benzene-1-sulfonyl chloride (2X 84. mu. mol). After purification by preparative reverse phase LC-MS and lyophilization, 10mg of example 101 was obtained and characterized by HPLC-MS, analytical method A as described above.
For analytical data see example 101 in table 1.
Example 105 as shown in table 1.
Similar to the procedure of example 100, but using 22mg of example 28 (free base; 25. mu. mol), 16mg of sodium carbonate (144. mu. mol) and 34mg of 4-methylpiperazine-1-sulfonyl chloride (144. mu. mol) in THF. After purification by preparative reverse phase LC-MS and lyophilization, 5mg of example 105 was obtained and characterized by HPLC-MS, analytical method a as described above.
For analytical data see example 105 in table 1.
Preparation of intermediate (II).
52mg of N, N' -disuccinimidyl carbonate (free base; 202. mu. mol) are suspended in 2ml of dry CH2Cl2Cooled to 0 ℃ and 32. mu.l of DIPEA (185. mu. mol) were added. 150mg of example 28 (168. mu. mol) were then added to 2.5ml of dry acetonitrile/CH2Cl2The solution in (1:1) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 7 hours, then an additional 15. mu.l of DIPEA (84. mu. mol) and 22mg of N, N "-disuccinimidyl carbonate (84. mu. mol) were added. The suspension was stirred at room temperature overnight, then concentrated, precipitated and washed twice with diethyl ether to give 177mg of crude (II) as a white solid.
As in example 97 shown in table 1.
25mg of succinimidyl carbamate (II) (26. mu. mol) and 9. mu.l of 2-methoxy-N-methylethylamine (77. mu. mol) are combined in 1ml of dry THF. The reaction mixture was stirred at room temperature for 2 hours, concentrated, and purified by preparative reverse phase LC-MS as described above. After lyophilization, 8mg of example 97 was obtained and characterized by HPLC-MS, analytical method A as described above. For analytical data see example 97 in table 1.
As in example 98 shown in table 1.
Similar to the procedure of example 97, but using 20mg of (II) (21. mu. mol) and 6. mu.l of morpholine (62. mu. mol). After purification by preparative reverse phase LC-MS and lyophilization, 3mg of example 98 was obtained and characterized by HPLC-MS, analytical method A as described above. For analytical data see example 98 in table 1.
As in example 99 shown in table 1.
Similar to the procedure of example 97, but using 20mg of (II) (21. mu. mol) and 7. mu.l of N-methylpiperazine (62. mu. mol). After purification by preparative reverse phase LC-MS and lyophilization, 7mg of example 99 was obtained and characterized by HPLC-MS, analytical method a as described above. For analytical data see example 99 in table 1.
Such as example 106 shown in table 1.
To a solution of 40mg of example 28 (42. mu. mol) and 22. mu.l of DIPEA (127. mu. mol) in 1.0ml of dry THF was added 6.1mg of 1H-imidazole-4-carbaldehyde (63. mu. mol). After 5 hours at room temperature, 3.2mg of sodium borohydride (85 μmol) was added and the reaction mixture was monitored to completion (about 15 minutes). A few drops of water were added and the mixture was concentrated and purified by preparative reverse phase LC-MS as described above. After lyophilization, 13mg of example 106 was obtained as a white solid and characterized by HPLC-MS, analytical method D as described above.
For analytical data see example 106 in table 1.
2. Biological method
2.1 preparation of peptide samples.
The lyophilized peptide was weighed on a microbalance (Mettler MX5) and dissolved in 90% aqueous DMSO to give a final concentration of 10mM (unless otherwise indicated). The stock solution was kept at +4 ℃ protected from light.
2.2CCR10 antagonism test
Peptides were tested for CCR10 antagonism in the calcium flux assay and in the tropism assay using a mouse pre-B cell line 300-19 stably transfected with human CCR10 and human CCL27 as an agonist.
Calcium flow test
Calcium flux release was assessed using 300-19 mouse pre-B cells transfected with CCR 10. These cells were labeled with Calcium4 reagent (Molecular Devices, Sunnyvale, Calif.) in HBSS buffer for 60 minutes as one batch.
Disperse 8X10 in each well of 384-well blackboard4After each cell, a concentrated solution of β -hairpin peptidomimetics of the invention in HBSS +0.1% BSA +0.1% DMSO (final concentration) was added to the cells the whole plate was centrifuged and placed on a Flexstation II (Molecular Devices) automatic plate reader after 20 second baseline reading, the Flexstation dispersed CCL27(RnDsystem) on the cells at 30nM final concentration in HBSS +0.1% BSA and calcium flow was measured for an additional 70 seconds.
Alternatively, the 384 well plates are read using FlipR384(Molecular Devices). In this case, about 8x10 would be4The cells of (a) were placed in each well, centrifuged, placed in a FlipR, and after a baseline reading of 5 seconds, β -hairpin peptidomimetics in HBSS +0.1% BSA +0.1% DMSO (final concentration) were added after an incubation time of 5 minutes, a CCL27 solution was added to the mixture and calcium flow was measured for 200 seconds.
The maximum signal was determined from control wells without inhibitor. Percent inhibition was calculated from a range of compounds, which range was then used to calculate IC50Value (Softmax Pro, Molecular Devices). All steps were performed at room temperature.
Tropism test
Disposable with Costar (5 μm pore size)Test plate CCR10 transfected 300-19 mouse pre-B cells were assayed for tropism response to a CCL27(CTACK) gradient according to the manufacturer's procedure. Briefly, cells were plated in flasks with RPMI +5% FCS, glutamine, penicillin/streptomycin (all media components from Life Technologies) and appropriately selected antibiotics (puromycin, G418 or tetracycline) in 5% CO2At 37 ℃. For testing, cells were pelleted by centrifugation, washed once in Dulbecco's Phosphate Buffered Saline (DPBS), and resuspended to give 1X 10 in RPMI +0.5% Bovine Serum Albumin (BSA)6Cell/ml 100. mu.l of cell suspension was applied to the test filter β -hairpin peptidomimetics diluted in the same test medium were added to the top and bottom of the chamber cells were allowed to float at 4 ℃ at 37-Transfer into the bottom chamber of the test plate containing 30nM CCL27(RnD system) at 6 hours the migrated cells were counted using a FACS flow cytometer (Cytomics FC500, Beckman Coulter) data normalisation was performed using the number of any cells migrating without β -hairpin peptidomimetics and the number of cells migrating randomly without CCL27 [ these values are 100% (no inhibitory activity) and 0%, respectively%]. IC was determined from a range of compound concentrations using Prism5(GraphPad software)50。
2.3 results
Table 2: biological results
TABLE 2 biological results (continuation)
TABLE 2 biological results (continuation)
TABLE 2 biological results (continuation)
nd = not determined

Claims (20)

1. A compound of the general formula (I)
Wherein a single element T or P is linked in either direction from the carbonyl (C ═ O) attachment point to the nitrogen (N) of the next element, and wherein
T1Is thatDPro；DPip; orDAze；
T2Is Pro;DPro；Oic；Pip；Tic；Tic(7OH)；Thz；Thz(5,5Me2)；Pro((4S)F)；Pro(5,5Me2) (ii) a Pro ((4S) cHex); pro ((4R) Ph); pro ((4R) Bn); pro ((4R)4BrBn); pro ((4R)3CNBn); hyp (Ph); hyp (Bn); hyp (4BrBn); hyp (3CNBn); hyp (4CNBn); hyp (conhph); or (4S) -Hyp (Bn);
P1and P3Independently are:
Phe；Phe(4Cl)；Phe(4F)；Phe(4CN)；Phe(3CF3)；Phe(4CF3)；Phe(4COOMe)；Trp；
trp (5OH); trp (6Cl); tyr; tyr (Me) Tyr (Ph); tyr (4OHPh); tyr (4MeOCOBN); hTyr; ala (2 furyl); ala (2Quin);2Nal; nle (6OBn);DLtrp (7Aza); cha; bip; bbta; or OctG;
P2is Aib; ac3c; ac4c; cyp; chx; chx (4oxo); ac7c; ac8c;DLatc; deg, respectively; or 4,4-AC-ThioTHP;
P4is Arg; hArg; ala (Ppz); thr; alloThr; gln; gln (ipr); gln (cpr); glu (Ala); glu (DAla)；Glu(Arg)；Glu(DArg)；Glu(Glu)；Glu(Gly)；Glu(His)；Glu(Leu)；Glu(DLeu)；Glu(2Nal)；Glu(Sar)；Glu(Trp)；Glu(DTrp)；Cys；hCys；Ser；hSer；Ser(Me)；hSer(Me)；Thr；Met；Met(O2)；Lys；hLys；Lys(Ac)；Lys(Me)；Lys(Bz)；Lys(Nic)；Lys(4Oxa)；Lys((5R)OH)；Dap；Dap(MeO(CH2)2)；Dap(CONH2)；Dap((MeO(CH2)2)2)；Dab；Dab(Ac)；Dab(morphCO)；Dab(MePpzCO)；Dab(MEMCO)；Dab(MeO(CH2)2NHCO)；Dab((MeO(CH2)2)(Me)NCO)；Dab(MeSO2)；Dab(4Me2NPhSO2) (ii) a Dab (dab); or Dab (SN13);
or His; hHis;2Pal;3Pal; or 4Pal;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, selected from:
cyclo (-Trp-Aib-Trp-Arg-)DPro-Tic-)；
Cyclo (-Trp-Aib-Trp-Dab-DPro-Tic-)；
Cyclo (-Trp-Cyp-Trp-Arg-)DPro-Tic(7OH)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4S)F)-)；
Cyclo (-Trp-Cyp-Trp-Arg-)DPro-Thz-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Thz-)；
Cyclo (-Trp (5OH) -Cyp-Trp-Gln-DPro-Thz-)；
Cyclo (-Trp (5OH) -Cyp-Trp-Arg-DPro-Tic-)；
Cyclo (-2Nal-Cyp-Trp-Gln-DPro-Tic-)；
Cyclo (-2Nal-Cyp-Trp-Dab-DPip-Pip-)；
Cyclo (-Trp (5OH) -Chx-Trp (5OH) -Arg-DPro-Oic-)；
Cyclo (-Trp (5OH) -Cyp-Trp (5OH) -Dap-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPip-Oic-)；
Cyclo (-Trp-Cyp-2Nal-Dab-DPip-Oic-)；
Cyclo (-Trp-Cyp-2Nal-Gln-DPro-Oic-)；
Cyclo (-OctG-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Gln-DPro-Oic-)；
Cyclo (-Trp-Chx-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Ac3c-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Ac4c-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-4,4-AC-ThiothP-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Phe (4F) -Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Tyr (Me) -Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Ala (2Quin) -Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Arg-)DAze-Tic-)；
Cyclo (-Trp-Cyp-Trp-Dab-DAze-Tic-)；
Cyclo (-Cha-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp (5OH) -Cyp-Trp-Arg-DPro-Thz(5,5Me2)-)；
Cyclo (-Trp-Atc-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Ala (2 furyl) -Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Phe (4F) -Ser-DPro-Oic-)；
Cyclo (-Trp-Cyp-Phe (4Cl) -Ser-DPro-Oic-)；
Cyclo (-Trp-Cyp-Phe (4CF3) -Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-DLTrp (7Aza) -Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Tyr (Ph) -Dab-DPro-Oic-)；
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPip-Pro((4R)Ph)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4R)Bn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4R)4BrBn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4R)3CNBn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro((4S)cHex)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro(5,5Me2)-)；
Cyclo (-Trp-Cyp-Phe (4Cl) -Dab-DPro-Hyp(Bn)-)；
Cyclo (-Phe (4CN) -Cyp-Phe (4F) -Ser-DPro-Hyp(Bn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(Bn)-)；
Cyclo (-Trp-Cyp-Trp-Ser-DPro-Hyp(Bn)-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Gln-DPro-Hyp(Bn)-)；
Cyclo (-Trp (6Cl) -Cyp-Trp-Dab-DPro-Hyp(Bn)-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Hyp(Bn)-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Ser-DPip-Hyp(Bn)-)；
Ring (addition)Trp-Cyp-Trp-Dab-DPro-(4S)-Hyp(Bn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(Ph)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(4CNBn)-)；
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPro-Hyp(4BrBn)-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Ser-DPro-Hyp(4BrBn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(4BrBn)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(CONHPh)-)；
Cyclo (-Trp-Cyp-Trp-alloThr-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-hArg-)DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-hCys-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Gln (iPr)) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-hSer (Me) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys (Ac) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys (Bz) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys (Me) -one-stepDPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys ((5R) OH) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys (Nic) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Met (O)2)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Ala (Ppz) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dap (CONH)2)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-dab (dab) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-dab (MEMCO) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab (MeO (CH))2)2NHCO)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dap (MeO (CH))2)2)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dap ((MeO (CH))2)2)2)-DPro-Oic-)；
Ring (-Ph (4COOMe) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp(3CNBn)-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Ser-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Ser-DPip-Oic-)；
Cyclo (-Trp (6Cl) -Cyp-Trp-Ser-DPro-Oic-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Ser-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys (4Oxa) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Ser (Me) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Thr-)DPro-Oic-)；
Cyclo (-Bip-Cyp-Trp-Dab-DPro-Oic-)；
Loop (-hTyr-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Bbta-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Nle (6OBn) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Tyr (4OHPh) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Tyr (Ph) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Tyr (4MeOCOBN) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Deg-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Ac7c-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Chx (4oxo) -Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Ac8c-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab ((MeO (CH))2)2)(Me)NCO)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-dab (morphCO) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-dab (MePpZCO) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab (MeSO)2)-DPro-Oic-)
Cyclo (-Trp-Cyp-Trp-Dab (4 Me)2NPhSO2)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-dab (Ac) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Hyp-)；
Cyclo (-Trp-Cyp-Trp-Dap-DPro-Oic-)；
Ring (-Trp-Cyp-Trp-Dab (SN13) -DPro-Oic-)；
Or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2, selected from:
cyclo (-Cha-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPip-Pro((4R)Ph)-)；
Cyclo (-Trp-Cyp-Trp-Dab-DPro-Pro(5,5Me2)-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Hyp(Bn)-)；
Cyclo (-Trp-Cyp-Trp-Met (O)2)-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Dap (CONH)2)-DPro-Oic-)；
Cyclo (-Phe (4CN) -Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-Lys (4Oxa) -DPro-Oic-)；
Cyclo (-Trp-Cyp-Trp-dab (MePpZCO) -DPro-Oic-)；
Or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1, selected from:
ring (-Trp-Cyp-Trp-Dab (A55) -DPro-Oic-)；
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Phe (4 CF)3)-Cyp-Trp-Dab(A56)-DPro-Oic-)；
Cyclo (-Phe (3 CF)3)-Cyp-Trp-Dab-DPro-Oic-)；
Cyclo (-Phe (4 CF)3)-Cyp-Trp-3Pal-DPic-Oic-)；
Or a pharmaceutically acceptable salt thereof.
5. Diastereomers, epimers and enantiomers of the compound of formula (I) as defined in claim 1.
6. Compounds according to any one of claims 1 to 5 for use as therapeutically active substances.
7. A compound according to any one of claims 1 to 5 having antagonistic activity against the CCR10 receptor.
8. A compound according to any one of claims 1-5, which selectively interferes with the natural activity of the CCR10 receptor and its natural ligands CCL27 and/or CCL 28.
9. A pharmaceutical composition comprising a compound or mixture of compounds according to any one of claims 1 to 5 and a pharmaceutically inert carrier.
10. The composition of claim 9 in a form suitable for oral, topical, transdermal, injection, transmucosal, or pulmonary administration.
11. The composition of claim 9 in a form suitable for buccal or rectal administration.
12. The composition of claim 9 in a form suitable for administration by inhalation.
13. A composition according to claim 9 in the form of a tablet, lozenge, capsule, solution, gel, plaster, cream, ointment, syrup, suspension, spray, nebuliser or suppository.
14. The composition of claim 9 in the form of a liquid.
15. The composition of claim 9 in the form of a slurry.
16. Use of a compound according to any one of claims 1-5 in the manufacture of a medicament for the treatment or prevention of skin disorders, metabolic diseases, inflammatory diseases, neurological diseases, respiratory diseases, gastrointestinal disorders, ocular diseases, hematological diseases and cancer mediated or maintained by the activity of CCR 10.
17. Use of a compound according to any one of claims 1-5 in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by the activity of CCR10 associated with an immune response in the field of inflammation, a skin disorder or cancer.
18. Use of a compound according to any one of claims 1-5 for the preparation of a medicament for the treatment or prevention of psoriasis, atopic dermatitis, contact and allergic dermatitis, Stewart-Johnson syndrome, bullous skin diseases, systemic lupus erythematosus, systemic and multiple sclerosis, allergic asthma, arthritis, graft-versus-host disease, melanoma and cutaneous lymphomas, inflammatory processes of the gastrointestinal tract and the eye mediated by the activity of CCR 10.
19. A process for preparing a compound according to any one of claims 1 to 5, comprising:
(a) coupling a suitably functionalized solid support to a suitably N-protected derivative of an amino acid at position T as defined above in the desired end product1Or T2Or P1To P4(ii) a Any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;
(b) removing the N-protecting group from the product obtained in step (a);
(c) coupling the product thus obtained to a suitable N-protected derivative of an amino acid which, in the desired end product, is in the position T or P of the next element, according to the sequence of formula (I) in the counter-clockwise or clockwise direction, in the direction of-COOH to-NH 2; any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;
(d) removing the N-protecting group from the product thus obtained;
(e) repeating steps (c) and (d) until all amino acid residues have been introduced;
(f) if desired, selectively deprotecting one or several of the protected functional groups present in the molecule and chemically converting the reactive groups thus released;
(g) detaching the product thus obtained from the solid support;
(h) cyclizing the product cleaved from the solid support;
(i) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues, and if desired, any protecting groups that may otherwise be present in the molecule; and
(j) if desired, carrying out a further chemical transformation of one or more reactive groups present in the molecule;
(k) if desired, the product thus obtained is converted into a pharmaceutically acceptable salt or a pharmaceutically acceptable or unacceptable salt thus obtained is converted into the corresponding free compound of formula (I) or into a different pharmaceutically acceptable salt.
20. The process of claim 19 for the preparation of a stereoisomeric compound according to claim 5, wherein a stereoisomer of a chiral starting material is used.
HK12111862.8A 2009-11-20 2010-11-18 Template-fixed peptidomimetics with ccr10 antagonistic activity HK1171036B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EPPCT/EP2009/065572 2009-11-20

Publications (2)

Publication Number Publication Date
HK1171036A HK1171036A (en) 2013-03-15
HK1171036B true HK1171036B (en) 2017-09-15

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