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WO2009097893A1 - Procédés de traitement d'une maladie cardiaque associée à une fibrose myocardique à l'aide d'un inhibiteur de pcp - Google Patents

Procédés de traitement d'une maladie cardiaque associée à une fibrose myocardique à l'aide d'un inhibiteur de pcp Download PDF

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WO2009097893A1
WO2009097893A1 PCT/EP2008/051347 EP2008051347W WO2009097893A1 WO 2009097893 A1 WO2009097893 A1 WO 2009097893A1 EP 2008051347 W EP2008051347 W EP 2008051347W WO 2009097893 A1 WO2009097893 A1 WO 2009097893A1
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alkyl
aryl
mono
aralkyl
group
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Begoña LÓPEZ SALAZAR
Arantxa GONZÁLEZ MIQUEO
Domingo Francisco Javier Diez Martinez
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Proyecto de Biomedicina CIMA SL
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Proyecto de Biomedicina CIMA SL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention relates to the methods for the treatment of myocardial diseases associated with increased fibrosis using PCP inhibitors.
  • the invention also relates to a method for providing a personalized therapy of diseases related to an increased fibrosis which involving the determination of a parameter associated with PCP activity.
  • HHT hypertensive heart disease
  • WO07146981 describes 4-heterocyclyl 2-arylamino-aminopirimidines derivatives which are able to reduce cardiac failure. These compounds act by the activity of protein kinase C.
  • WO07129646 describes different macro lides which are suitable for the treatment of chronic cardiac failure. These compounds are believes to exert their therapeutic properties by inhibition of the matrix metalloprotease -9.
  • JP2007204416 describes the use of compositions comprising isoleucine, valine and leucine for the treatment of chronic cardiac failure.
  • US2007072825 describes the use of N-bencilpiridine -modified porf ⁇ rinic compounds for the treatment of cardiovascular diseases, including chronic cardiac failure.
  • US2006111361 describes a method for reverting left ventricle remodeling occurring during chronic cardiac failure by the administration of ranolazine or of a combination of ranolazine and enalapril or of ranolazine and metoprolol tartrate.
  • WO07072564 describes a method for the treatment and prevention of chronic cardiac failure by the use of voglibose o acarbose, two compounds which exert their therapeutic effects due to their antihyperglycemic effect caused by an inhibition of the glycosidase ⁇ activity.
  • WO07077122, WO07006688 and WO07039438 describe methods for the treatment of chronic cardiac failure based on the use of antagonists of the vasopressin Via receptor, in particular, compounds carrying a indol-3-carbonyl-spiro group
  • WO05087233 describes a method for the treatment of chronic cardiac failure based on the administration of perhexiline, a known antianginal agent capable of modifying cardiac metabolism from a free fatty acid-based metabolism to the more efficient glucose-based metabolism.
  • WO04060489 describes a method for the treatment of chronic cardiac failure based on the administration of xanthine oxidase inhibitor, which results in an increase of the high-energy phosphate available to the cardiac muscle
  • US2006094715 describes a method for the treatment and prevention of chronic cardiac failure based on the administration of 5-HT 4 receptor antagonists.
  • US2004082641 describes a method for the treatment and prevention of early cardiovascular diseases, including chronic cardiac failure, based on the administration of inhibitors or glycogen phosphorylase.
  • WO04105786 describes a method for the treatment of chronic and acute cardiac failure un based in the administration of adiponectine, isolated or in combination with an agent such as pentoxifylline, which is capable of regulating the production of tumor necrosis factor ⁇ .
  • Fenofibrate an agonist of the peroxisomal proliferator alpha receptor
  • Fenofibrate an agonist of the peroxisomal proliferator alpha receptor
  • statins are capable of decreasing cardiac fibrosis in hypertensive rats. Preliminary results indicate that this anti-f ⁇ brotic effect is the result of a direct effect in signals causing fibroblast activation and growth (Porter et al., Cardiovasc Res 2004; 61 :745- 755). Swaney, et al.
  • the invention relates to a method for the treatment or prevention of a cardiac disease associated to myocardial fibrosis in a subject comprising the administration of a therapeutically effective amount of an agent which is capable of inhibiting PCP.
  • the invention relates to a method for developing a personalized therapy for the treatment of a patient suffering from a cardiac disease associated to myocardial fibrosis comprising:
  • PCP activity and (b) if the value of said parameter is higher than a predefined threshold value, then the patient is candidate to the treatment with a therapeutically effective amount of a PCP inhibitory agent.
  • Figure 1 Schematic representation of the steps involved in the synthesis and processing of collagen type I molecules.
  • DNA deoxyribonucleic acid
  • PCP procollagen type I carboxy-terminal proteinase
  • PCPE procollagen type I carboxy-terminal proteinase enhancer
  • PICP carboxy- terminal propeptide of procollagen type I, that is released as result of the action of PCP on its substrate and secreted into the blood stream.
  • Figure 2 Western blots and autoradiograms of PCP.
  • Figure 3 Western blots and autoradiograms of PCPE.
  • FIG. 4 PCP and PCPE expression.
  • Figure 5 Association between aldosterone and PCP activation.
  • Figure 7 Associations among PCP activation and CVF and PICP.
  • torasemide is capable of interfering with the myocardial PCP/PCPE system and that said effect may be one of the factors contributing to the therapeutic effect on myocardial diseases.
  • the invention relates to a method for the treatment or prevention cardiac disease associated to myocardial fibrosis in a subject comprising the administration of a therapeutically effective amount of an agent which is capable of inhibiting PCP.
  • PCP is understood as the type I procollagen carboxyterminal proteinase, a zinc protease secreted by fibroblasts in response to TGF ⁇ activation.
  • PCP belongs to the family of astacin-related proteases and is capable of cleaving the C-terminal peptide of type I, II and III collagens. Additionally, PCP is capable of activating lysyl oxidase, an enzyme essential for the cross-linking of the collagen fibers which stabiles the structure of collagen.
  • lysyl oxidase an enzyme essential for the cross-linking of the collagen fibers which stabiles the structure of collagen.
  • PCP plays a double role in collagen formation since it converts procollagen precursor molecules into the units that can associate to form collagen fibers and promoter the cross-linking among the collagen fibers.
  • PCP inhibitor is understood as a compound capable of inhibiting the capacity of PCP of activating type I, II and YYY collagen.
  • the PCP inhibitors useful in the context of the present invention show IC50 values within the range of about 0.001 ⁇ M to about 100 ⁇ M.
  • the inhibitors have IC50 values within the range of about 0.01 ⁇ M to about 10.0 ⁇ M, more preferably, between about 0.1 ⁇ M and 1 ⁇ M.
  • tumour growth models Keratin-1 (Kiohs, et al., 1985, JNCL 75:353-359), trabeculectomy models (Lahery et al., 1989, Journal of Ocular Pharmacology 5:155-179) and abdominal adhesion model (Williams et al., 1992, J. Surg. Res. 2:65-70).
  • PCP inhibitors adequate in the context of the present invention include:
  • Rl is hydrogen or a methyl group.
  • Z is -OH, -NHOH, or OR 12 wherein R 12 is alkyl
  • R 3 and R 7 are, independently of each other, hydrogen, alkyl, alkylthio, or halo;
  • R 4 and R 6 are, independently of each other, hydrogen, alkyl, or halo;
  • R 5 is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy, cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfony
  • R 10 is hydrogen, alkyl, alkoxy, or halo
  • R 11 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino or alkylsulfonyl provided that both R 10 and R 11 are not hydrogen at the same time.
  • -heterocvclylpropanohidroxamic acid derivatives These compounds, described in US6645993, show a general structure of the formula:
  • X is alkylene or alkenylene, each of which is unsubstituted or substituted by one or more fluorine atoms;
  • R is aryl, cycloalkyl or cycloalkenyl unsubstited or substituted by one or more fluorine atoms W is N,
  • Y 1 is alkyl, unsubstituted or substituted by aryl, or by one or more halogen atoms, with the proviso that when Y 1 is methyl, X 1 is not H; or Y 1 is aryl; or
  • Y 1 is a mono or bicyclic non-aromatic carbocyclic or heterocyclic moiety containing up to 10 ring atoms and which can include up to 3 ring heteroatoms, independently selected from N, O and S, which ring moiety is unsubstituted or substitued by one or more substituents independently selected from halogen, alkoxy and alkyl unsubstituted or substituted by one or more halogen; aryl is a mono or bicyclic aromatic carbocyclic or heterocyclic moiety containing up to 10 ring atoms, and which can include up to 3 ring heteroatoms, independently selected from N, O and S, which ring moiety is unsubstituted or substituted by one or more substitutents, independently selected from halogen, alkoxy and Ci-C 4 alkyl unsubstituted or substituted by halogen.
  • X is alkylene or C C alkenylene, each of which is unsubstituted or substituted by one or more fluorine atoms;
  • [HET] is a divalent heterocyclic moiety selected from:
  • Z is H or C 1"4 alkyl
  • X is alkylene or alkenylene, each of which is optionally substituted by one or more fluorine atoms;
  • R is aryl or C C cycloalkyl optionally substituted by one or more fluorine atoms; W is N or CZ; Y and Z are each independently H, C 1 -C 4 alkyl (optionally substituted by one or more substituents independently selected from halogen, S(O)pR 6 , OR 5 , CONR 1 R 2 , o CO 2 R 7 and aryl), alkanoyl optionally substituted by one or more halogen, alkoxycarbonyl optionally substituted by one or more halogen or CONR 1 R 2 , R 1 and R 2 are each independently selected from H cycloalkyl, alkyl (optionally substituted by C 3 -C 8 cycloalkyl, aryl, CO 2 H, CO 2 R 5 , and/or NR 3 R 4 ), or R 1 and R 2 can be taken together with the nitrogen to which they are attached to represent a 4- to 6-membered heterocyclic ring optionally containing one or two further hetero atom
  • R 3 and R 4 are each independently selected from H, C alkyl or alkoxycarbonyl optionally substituted by one or more halogen, or R 3 and R 4 can be taken together with the nitrogen atom to which they are attached to represent a morpholine, piperidine, azetidine or piperazine (optionally N-substituted by
  • R 5 is alkyl optionally substituted by CO 2 R 7 , CONR 3 R 4 , o R 5 is aryl;
  • R 6 is alkyl optionally substituted by one or more halogen, or aryl;
  • R 7 is H or R 6 ;
  • p is 0, 1 or 2
  • Aryl is a mono- or bicyclic aromatic carbocyclic or heterocyclic system comprising from 5 to 10 ring atoms, including up to 3 hetero-atoms selected from N, O and S, where, if there is a N atom in the ring, it can be present as the N-oxide, which ring system is optionally substituted by up to 3 substituents independently selected from halogen, Ci-C 4 alkyl optionally substituted by one or more halogen, Ci-C 4 alkoxy optionally substituted by one or more halogen, phenyl, pyridyl, CO 2 H,
  • CONR 3 R 4 CO 2 (Ci-C 4 alquilo), NR 3 R 4 , OH y OC(O)(Ci-C 4 alquilo).
  • Ri is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, halo substitituted aralkyl, heteroaralkyl, biaryl, biarylalky, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalAyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(tio, sulfmyl or sulfonyl)-alkyl;
  • R 2 is selected from the group consisting of H, lower alkyl
  • R 3 is selected f ⁇ om the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, halo substitituted aralkyl, heteroaralkyl, biaryl, biaryialkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl; R 4 is selected from the group consisting of aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl,
  • Y is selected from the group consisting of OH, HOHN (hydroxylamine), H 2 N, alkylamino; Z s a direct bond; methylene, oxygen, sulfur, amino; and n is 0 or 1.
  • Ri is selected from the group consisting of H, lower alkyl, mono- or poly-haloalhyl, carboxyalkyl, aryi, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoallcyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulf ⁇ nyl or sulfony l)-alkyl;
  • R 2 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfony l)-alkyl;
  • R 3 is selected f ⁇ om the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalk ⁇ l, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialLylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalAylalkyl, heterocycloalkylalkyl , alkyl-(thio, sulf ⁇ nyl or sulfony l)-alkyl;
  • R 4 is selected from the group consisting of H, lower alkyl
  • R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylarnino)alkyl, alkyl-(thio, suf ⁇ nyl or sulfonyl)alkyl, alkoy alky lacy lalkyl.
  • Ri is selected from the group consisting of H, lower alkyl, mono- or poly-haloalhyl, carboxyalkyl, aryi, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoallcyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulf ⁇ nyl or sulfony l)-alkyl;
  • R 2 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfony l)-alkyl;
  • R 3 is selected f ⁇ om the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalk ⁇ l, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialLylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalAylalkyl, heterocycloalkylalkyl , alkyl-(thio, sulfmyl or sulfony l)-alkyl;
  • R 4 is selected from the group consisting of H, lower alkyl
  • R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylarnino)alkyl, alkyl-(thio, suf ⁇ nyl or sulfonyl)alkyl, alkoy alky lacy lalkyl.
  • Ri is selected from the group consisting of H, lower alkyl, mono- or poly-haloalhyl, carboxyalkyl, aryi, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoallcyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulf ⁇ nyl or sulfony l)-alkyl;
  • R 2 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulf ⁇ nyl or sulfony l)-alkyl;
  • R 3 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalk ⁇ l, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalAylalkyl, heterocycloalkylalkyl , alkyl-(thio, sulfmyl or sulfony l)-alkyl;
  • R 4 is selected from the group consisting of H, lower alkyl
  • R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylamino)alkyl, alkyl-(thio, suf ⁇ nyl or sulfonyl)alkyl, alkoyalkylacylalkyl.
  • R 1 and R 4 are, independently of each other, hydrogen or alkyl; R 2 is
  • R 3 is hydrogen or alkyl
  • R 6 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl
  • R 5 is
  • R 5 and R 4 form an alkylene chain; or (iii) R 5 and R 6 form an alkylene chain; n is 0 ⁇ 1
  • R 9 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, hetergcycloalkyl, heteroalkyl, or -(alkylene)-C(O)-X 1 where X 1 is alkyl, hydroxy, alkoxy, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy or NRR" (where R and R" are independently H or alkyl, or R and R" form an alkylene chain) R 10 is hydrogen, alkyl, aralkyl or heteroaralkyl; Z is Y-B wherein
  • Y is alkylene or a bond
  • B is -CO-, -C(O)O-, -CONR 8 -, -SO 2 -, o -SO 2 NR 8 - (wherein R 8 is hydrogen or alkyl), alkylene (optionally substituted by hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or a bond;
  • the application relates to methods of treatment using the compounds as defined above, alone or in combination of one or more as well as methods of treatment using their salts, solvates, hydrates or prodrugs.
  • Suitable acid addition salts are formed from acids which form non-toxic salts and include the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, hydrogenphosphate, acetate, trifluoroacetate, gluconate, lactate, salicylate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, gluconate, formate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, pamoate, carasylate, and p- toluenesulphonate salts.
  • base addition salts are well known to those skilled in the art, and for example include those mentioned in the art cited above, and can be formed from bases which form non-toxic salts and include the aluminium, calcium, lithium, magnesium, potassium, sodium and zinc salts, as well as alkaline organic salts such as diethanolamine, ethanolamine, triethanolamine, glucamine and basic amino acid salts.
  • PCP inhibitory agents suitable for the methods of the invention may exist in one or more zwitterionic forms. Certain of the compounds may exist in one or more tautomeric forms. Certain of the compounds, their salts, solvates, prodrugs, etc. may exist in one or more polymorphic forms. It is to be understood that the methods of the invention contemplate the use of all such zwitterions, tautomers and polymorphs of the compounds mentioned above. Certain of the PCP inhibitory compounds suitable for use in the methods of the invention can be used in crystalline form or as solvates (e. g. hydrates) and it is intended that both forms be within the scope of the present invention.
  • solvate defines a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Methods of solvation are generally known within the art.
  • the compounds for use in the methods of the invention can exhibit isotopic variation, e.g. forms with enriched 2 H, 13 C, 14 C, 15 N, 18 O and the like may be prepared, for example by suitable variation of the synthetic methods described herein using methods and reagents known in the art or routine modification thereof. All such isotopic variants are included in the scope of the invention.
  • Prodrug moieties are well-known to those skilled in the art (see for example the article by H Feres, in Drugs of Today, vol 19, no.9 (1983) pp.499-538, especially section Al), and for example include those specifically mentioned in A.A. Sinkula's article in Annual Reports in Medicinal Chemistry, vol 10, chapter 31, pp.306-326, herein incorporated by reference, and the references therein.
  • Specific prodrug moieties which may be specifically mentioned are aliphatic-aromatic, carbonate, phosphate and carboxylic esters, carbamates, peptides, glycoside, acetals and ketals, tetrahydropyranyl and silyl ethers. Such prodrug moieties can be cleaved in situ, e.g. are hydrolysable in physiological conditions, to give compounds listed above.
  • Certain of the compounds suitable for the methods of the invention may exist as geometric isomers.
  • the compounds of the formula (I) may possess one or more asymmetric centers, apart from the specified centers in formula (I), and so exist in two or more stereoisomeric forms.
  • the present invention includes all the individual stereoisomers and geometric isomers of the compounds and mixtures thereof.
  • the compounds listed above or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%.
  • the purity is above 95% of the compound or of its salts, solvates or prodrugs.
  • the compounds used in the methods of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds are outweighed by the therapeutically beneficial effects.
  • the actual amount of the compound i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, preferably once or twice a day.
  • Therapeutically effective amounts of compounds used in the methods of the invention may range from approximately 0.05-35 mg per kilogram body weight of the recipient per day; preferably about 0.3-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 21 mg to 1.4 g per day.
  • the choice of the optimal route of administration of the pharmaceutical compositions will be influenced by several factors including the physico-chemical properties of the active molecules within the compositions, the urgency of the clinical situation and the relationship of the plasma concentrations of the active molecules to the desired therapeutic effect.
  • the PCP inhibitors may be prepared with carriers that will protect them against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can inter alia be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid.
  • the PCP inhibitors may be necessary to coat the PCP inhibitors with, or coadminister the agonistic binding molecules with, a material or compound that prevents the inactivation of the PCP inhibitors.
  • the PCP inhibitors may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • the routes of administration of the PCP inhibitors can be divided into two main categories, oral and parenteral administration. These two categories include, but are not limited to, bolus, buccal, epidermal, epidural, inhalation, intra- abdominal, intra-arterial, intra-articular, intrabronchial, intracapsular, intracardiac, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebronventricular, intracolic, intracervical, intradermal, intragastric, intrahepatic, intramedullary, intramuscular, intramyocardial, intranasal, intra-ocular intra-orbital, intra-osteal, intrapelvic, intrapericardiac, intraperitoneal, intraplaque, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasternal, intrasynovial, intrathecal, intrathoracic, intratumoral, intra-uterine, intravenous,
  • Intranasal delivery is typically accomplished with dry powder formulations, liquid solutions or suspensions suitable for nebulization or with aerosol propellants suitable for use in a metered dose inhaler.
  • drug substance may be associated with microspheres made of materials such as gelatin, dextran, collagen or albumin
  • microspheres are conveniently delivered in freeze dried form with a nasal insufflator device or a pressurized aerosol cannister.
  • Penetration enhancers such as amphiphilic steroids may also be used as additives to increase the systemic absorption of the drug into the tissue. Effective administration may also be accomplished by pulmonary or respiratory delivery since polypeptides are readily absorbed through the cellular lining of the alveolar region of the mammalian lung. Advantageously, such administration frequently does not require the use of penetration enhancers as additives.
  • Devices and methods for pulmonary delivery deep into the lung are described in U.S. Pat. No. 5,780,014, issued JuI. 14, 1998 and U.S. Pat. No. 5,814,607, issued Sep. 29, 1998.
  • Oral dosage forms can be formulated inter alia as tablets, troches, lozenges, aqueous or oily suspensions, dispersable powders or granules, emulsions, hard capsules, soft gelatin capsules, syrups or elixirs, pills, dragees, liquids, gels, or slurries.
  • formulations can contain pharmaceutically excipients including, but not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid ; binding agents such as starch, gelatin or acacia; lubricating agents such as calcium stearate, glyceryl behenate, hydrogenated vegetable oils, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl, fumarate, stearic acid, talc, zinc stearate; preservatives such asn-propyl-p-hydroxybenzoate ; colouring, flavouring or sweetening agents such as sucrose, saccharine, glycerol, propylene glycol or sorbitol; vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil; mineral oils such as liquid paraf ⁇ n; wetting agents such as benzalkonium chloride,
  • compositions of the present invention can also be formulated for parenteral administration.
  • Formulations for parenteral administration can be inter alia in the form of aqueous or non-aqueous isotonic sterile non-toxic injection or infusion solutions or suspensions.
  • Preferred parenteral administration routes include intravenous, intraperitoneal, epidural, intramuscular and intratumoral injection or infusion.
  • the solutions or suspensions may comprise agents that are non-toxic to recipients at the dosages and concentrations employed such as 1,3-butanediol, Ringer's solution, Hank's solution, isotonic sodium chloride solution, oils such as synthetic mono-or diglycerides or fatty acids such as oleic acid, local anaesthetic agents, preservatives, buffers, viscosity or solubility increasing agents, water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like, oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like, and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
  • Transdermal delivery devices employ a structure such as an adhesive patch or the like that serves as a reservoir for the drug and brings the drug into diffusive contact with the skin.
  • the structure is a three dimensionally stable matrix known as a monolithic matrix.
  • Such matrices are described in more detail in U.S. Pat. Nos. 5,804,214, 5,149,538 and 4,956,171 which describe matrices made of polymers and copolymers of acrylic latexes, acrylic esters, methacrylic esters and vinyl acetates.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aide administration, and do not adversely affect the therapeutic benefit of the compound of formula (I).
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • the diseases that can be treated using the method of the invention include any disorder wherein there is an abnormal increase in the amount of collagen fibres in the myocardium.
  • Said disease is selected from the group of chronic cardiac failure and HHT.
  • the invention relates to a method for providing a personalized therapy for the treatment of a patient suffering from a cardiac disease associated to myocardial fibrosis comprising:
  • Parameters indicative of PCP activity are known to the skilled person.
  • said parameters can be selected from the group of:
  • PICP or carboxy terminal propeptide of type I procollagen corresponds to the peptide which is released from the procollagen type I alpha subunit upon cleavage of this molecule by PCP (see figure 1). Since PP activity is necessary for the generation of PICP, the levels of this peptide in a sample from a patient will show a positive correlation with the activity of PCP in said subject. Thus, increased PICP will be indicative of an increase fibrosis and hence, that the patient might benefit from a therapy aimed at inhibiting PCP activity.
  • Techniques suitable for detecting PICP in a sample include any technique capable of quantitative determination of a protein in a sample.
  • these assays are immunoassays using anti-PICP specific monoclonal or polyclonal antibodies.
  • Adequate techniques include RIA, ELISA, Western blotting, immunofluorescence, immunoturbidimetry, nepehelometry, turbidimetry, latex- amplified nepehelometry.
  • the RIA methods described by Melkko et al., (Clin.Chem., 1990, 36:1328-1332) and in GB2245568 are particularly preferred.
  • PCP activity in a sample of the patient can also be used as a parameter indicative on whether the patient will benefit from the treatment with a PCP inhibitor. Methods for determining PCP activity have been explained in detail above.
  • PCP levels and the ratio of mature PCP to PCP zymogen are also indicative of the activity of said protein since PCP is synthesized as a zymogen which requires proteolytic cleavage for activation.
  • PCP is synthesized as a zymogen which requires proteolytic cleavage for activation.
  • PCP to PCP zymogen it is possible to conclude whether the patient can be a candidate for the treatment with a PCP inhibitor.
  • the skilled person will appreciate that the determination of the levels of PCP must be carried out using techniques which allow the specific detection of said protein while avoiding the simultaneous detection of the inactive zymogen.
  • the determination of PCP and the PCP zymogen in a biological sample is carried out after fractionating the proteins of said sample based on their size followed by immunodetection with an antibody capable of binding to both PCP and to the zymogen. By detecting both proteins on the same experiment, it is possible to calculate the expression ratios.
  • the parameter indicative of PCP activity is the amount of the PCP enhancer (PCPE), a glycoprotein that binds PICP (Kessler, E. and Adar,R. 1989, Eur.J.Biochem., 186:115-121) and that stimulates PCP activity (Adar, R. et al., 1986, Collagen Relat. Res. 6:267-277).
  • PCPE PCP enhancer
  • the concentration of PCPE is an indication of the PCP overall activity and thus, by measuring the amount of PCPE activity, it is possible to determine the activity of PCP.
  • PCPE is measured using any of the methods known in the art for quantitative determination of a protein in a sample.
  • the levels of PCPE are determined by immunoassays using anti-PCPE specific monoclonal or polyclonal antibodies. Adequate techniques include RIA, ELISA, Western blotting, immunofluorescence, immunoturbidimetry, nepehelometry, turbidimetry and the like.
  • PCPE is determined by Western blot as shown in fig. 3.
  • the determination of the parameters indicative of PCP activity is carried out in any biological sample that contains sufficient amount of the proteins so that their presence can be detected either by measuring expression levels or by determining the activity.
  • the different parameters indicative of PCP activity can be determined in myocardial biopsies. However, it is preferred to determine the parameters on samples which do not require invasive methods for their preparation.
  • the parameter indicative of PCP activity is the PICP levels and said PCIP levels are determined in serum or plasma.
  • the invention relates to the methods of determining parameters associated to myocardial fibrosis using wherein said values are calculated in relation to a threshold value wherein said threshold value is the value of the parameter indicative of PCP activity in a patient which does not suffer of cardiac disease associated to myocardial fibrosis.
  • the PCP inhibitor which is selected based on the value of the parameter indicative of PCP activity is torasemide.
  • Torasemide is a pyridine- sulfonylurea type loop diuretic having the following formula:
  • the cardiac disease associated to myocardial fibrosis is selected from the group of chronic cardiac failure and HHT.
  • the study population consisted of 22 white patients. All patients were required to have a previous diagnosis of chronic HF by the presence of a least 1 major and 2 minor criteria of the Framingham study (Ho et al, 1993, J.Am.Coll.CardioL, 22 Suppl A:6A-13A) during the last 6 months. Whereas 80% of the patients enrolled had hypertensive heart disease, the remaining 20% showed ischemic heart disease. None of the patients had suffered from previous myocardial infarction. A depressed ejection fraction ( ⁇ 0.40) was observed in 55% of patients.
  • Echocardiographic assessment Two-dimensional echocardiographic imaging, targeted M-mode recordings, and Doppler ultrasound measurements were obtained in each patient as recommended (Sahn et al., 1978, Circulation, 58:1072-1083). Left ventricular mass was measured, and left ventricular mass index was calculated by dividing left ventricular mass by body surface area. The following pulsed Doppler measurements were obtained: maximum early transmittal velocity in diastole, maximum late transmittal velocity in diastole, the deceleration time of the early mitral filling wave, and isovolumic relaxation time. Ejection fraction was calculated according to
  • Biochemical determinations Venous blood samples were drawn at 09:00 h in an upright position. Plasma aldosterone was measured by radioimmunoassay using a commercial kit. Serum PICP was determined by radioimmunoassay according to a method previously described (Querejeta et al., Circulation, 2000, 101 :1729-1735). Histomorphologic and immunohistochemical studies.
  • RTPCR Reverse transcriptase-polymerase chain reaction
  • Real-time PCR was performed with an ABI PRISM 7000 Sequence Detection System according to the manufacturer's recommendations (Applied Biosystems, Madrid, Spain) by using specific TaqMan MGB fluorescent probes for human mRNA of the ⁇ l chain of procollagen type I (HsOO 176329), and a specific TaqMan MGB fluorescent probe for human constitutive 18s ribosomal RNA as endogenous control. Data are expressed as arbitrary units relative to 18s ribosomal RNA.
  • Baseline characteristics Baseline clinical and echocardiographic characteristics of the 2 groups of patients are presented in the Table 1.
  • PCP AND PCPE EXPRESSION The expression of both PCP zymogen and PCP active form increased (p ⁇ 0.05) in the furosemide group, but remained unchanged in the torasemide group (Table 3, Fig. 2). Whereas PCP activation remained unchanged in furosemide-treated patients (1.96 ⁇ 0.16), it decreased (p ⁇ 0.05) in torasemide-treated patients (2.14 + 0.19). The expression of full-length PCPE did not change with treatment in either group of patients (Table 3, Fig. 3). The 36-kDa PCPE fragment decreased (p ⁇ 0.05) in torasemide-treated patients and remained unchanged in furosemide-treated patients (Table 3, Fig. 3).

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Abstract

L'invention concerne des procédés de traitement de maladies cardiaques associées à la fibrose, en particulier à l'insuffisance cardiaque chronique ou à une maladie cardiaque hypertensive, par l'utilisation de composés qui sont capables de réduire l'activité de la procollagène protéinase C ou PCP. L'invention concerne également des procédés de développement d'une thérapie personnalisée pour le traitement d'un patient souffrant d'une maladie cardiaque associée à la fibrose myocardique, comportant la détermination dans un échantillon dudit patient d'un paramètre indicatif de l'activité PCP, et, si la valeur dudit paramètre est supérieure à une valeur de seuil prédéfinie, alors le patient est candidat au traitement par une quantité thérapeutique efficace d'un agent inhibiteur de PCP, en particulier par le torasémide.
PCT/EP2008/051347 2008-02-04 2008-02-04 Procédés de traitement d'une maladie cardiaque associée à une fibrose myocardique à l'aide d'un inhibiteur de pcp Ceased WO2009097893A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10414797B2 (en) * 2015-11-16 2019-09-17 Iproteos S.L Gelatinase inhibitors and use thereof
US10450288B2 (en) 2014-01-10 2019-10-22 Glaxosmithkline Intellectual Property (No. 2) Limited Hydroxy formamide derivatives and their use

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015166A1 (fr) * 1993-12-02 1995-06-08 Curators Of The University Of Missouri Emploi d'antagonistes d'aldosterone pour inhiber la fibrose myocardique
WO1997005865A1 (fr) * 1995-08-08 1997-02-20 Fibrogen, Inc. Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene
WO2000027277A1 (fr) * 1998-11-10 2000-05-18 Ineedmd.Com, Inc. Dispositif de telediagnostic
WO2000034313A1 (fr) * 1998-12-10 2000-06-15 F. Hoffmann-La Roche Ag Inhibiteurs de la c-proteinase de procollagene
WO2001047901A1 (fr) * 1999-12-23 2001-07-05 Pfizer Limited Acides ox(adi)azolyl-hydroxamiques utilises comme inhibiteurs de la procollagene c-proteinase
WO2002079175A1 (fr) * 2001-03-30 2002-10-10 Pfizer Limited Inhibiteurs pcp a l'acide 3-heterocyclyl-propanohydroxamique
US6492394B1 (en) * 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
US20030069291A1 (en) * 2001-03-30 2003-04-10 Simon Bailey 3-heterocyclylpropanohydroxamic acid PCP inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015166A1 (fr) * 1993-12-02 1995-06-08 Curators Of The University Of Missouri Emploi d'antagonistes d'aldosterone pour inhiber la fibrose myocardique
WO1997005865A1 (fr) * 1995-08-08 1997-02-20 Fibrogen, Inc. Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene
WO2000027277A1 (fr) * 1998-11-10 2000-05-18 Ineedmd.Com, Inc. Dispositif de telediagnostic
WO2000034313A1 (fr) * 1998-12-10 2000-06-15 F. Hoffmann-La Roche Ag Inhibiteurs de la c-proteinase de procollagene
US6492394B1 (en) * 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
WO2001047901A1 (fr) * 1999-12-23 2001-07-05 Pfizer Limited Acides ox(adi)azolyl-hydroxamiques utilises comme inhibiteurs de la procollagene c-proteinase
WO2002079175A1 (fr) * 2001-03-30 2002-10-10 Pfizer Limited Inhibiteurs pcp a l'acide 3-heterocyclyl-propanohydroxamique
US20030069291A1 (en) * 2001-03-30 2003-04-10 Simon Bailey 3-heterocyclylpropanohydroxamic acid PCP inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GONZÁLEZ ARANTXA ET AL: "New directions in the assessment and treatment of hypertensive heart disease", CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION, RAPID SCIENCE, LONDON, GB, vol. 14, no. 5, September 2005 (2005-09-01), pages 428 - 434, XP009097978, ISSN: 1062-4821 *
LOPEZ BEGONA ET AL: "Identification of a potential cardiac antifibrotic mechanism of torasemide in patients with chronic heart failure", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 50, no. 9, August 2007 (2007-08-01), pages 859 - 867, XP002476427, ISSN: 0735-1097 *
OVENS A ET AL: "Design and synthesis of acidic dipeptide hydroxamate inhibitors of procollagen C-proteinase.", JOURNAL OF PEPTIDE SCIENCE : AN OFFICIAL PUBLICATION OF THE EUROPEAN PEPTIDE SOCIETY SEP 2000, vol. 6, no. 9, September 2000 (2000-09-01), pages 489 - 495, XP002476431, ISSN: 1075-2617 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10450288B2 (en) 2014-01-10 2019-10-22 Glaxosmithkline Intellectual Property (No. 2) Limited Hydroxy formamide derivatives and their use
US10414797B2 (en) * 2015-11-16 2019-09-17 Iproteos S.L Gelatinase inhibitors and use thereof
AU2016356876B2 (en) * 2015-11-16 2020-10-01 Accure Therapeutics, S.L. Gelatinase inhibitors and use thereof

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