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WO1990007523A1 - Medicament contenant un cyclolinopeptide a - Google Patents

Medicament contenant un cyclolinopeptide a Download PDF

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Publication number
WO1990007523A1
WO1990007523A1 PCT/SE1989/000732 SE8900732W WO9007523A1 WO 1990007523 A1 WO1990007523 A1 WO 1990007523A1 SE 8900732 W SE8900732 W SE 8900732W WO 9007523 A1 WO9007523 A1 WO 9007523A1
Authority
WO
WIPO (PCT)
Prior art keywords
cla
mice
cyclolinopeptide
pbs
pfc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE1989/000732
Other languages
English (en)
Inventor
Zbigniew Wieczorek
Ignacy Z. Siemion
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ferring AB
Original Assignee
Ferring AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ferring AB filed Critical Ferring AB
Priority to KR1019900701862A priority Critical patent/KR910700263A/ko
Publication of WO1990007523A1 publication Critical patent/WO1990007523A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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

Definitions

  • the present invention relates to Cyclolinopeptide A for use as an immunosuppressive agent, to use of Cyclo ⁇ linopeptide A for the preparation of a medicament for immunosuppressive treatment, to a method of treating a mammal, including man, in need of immunosuppressive • treatment and to a pharmaceutical preparation comprising Cyclolinopeptide A.
  • Cyclolinopeptide A was first isolated from linseed cake by Kaufmann H.P- and Tobschirbel A., in 1959 (Chem. Ber. , ⁇ 2, 2805 (1959)) and its chemical structure was suggested in 1966 by Prox, A. and Weygand, F. [(1967) in "Peptides: Proceedings of the 8th European Peptide Symposium", Beyerman, H.C., van de Linde, A. and van den Brink, .M. Eds., North Holland, Amsterdam, pp.
  • the present invention is based on the finding that Cyclolinopeptide A (CLA) having the formula
  • Cyclolinopeptide A for use as an immunosuppressive agent.
  • a pharmaceutical preparation comprising Cyclo ⁇ linopeptide A together with pharmaceutically acceptable carrier(s), excipient(s) and/or diluent(s).
  • the amount of Cyclolinopeptide A to be administered to a mammal in need of immunosuppressive treatment has to be decided by a physician who is experienced in immuno ⁇ suppressive therapy.
  • the pharmaceutical preparation comprising Cyclolino- peptide A can be formulated into oral preparations or preparations for infusion using pharmaceutically accep ⁇ table carrier(s), excipient(s) and/or diluent(s) suitable for such preparations, but keeping in mind that Cyclo ⁇ linopeptide A is insoluble in water.
  • the pharmaceutical preparation can e.g. comprise Cyclolinopeptide A in a pharmacologically effective amount suspended in an olive oil.
  • Cyclolinopeptide A has immunosuppressive activity, which is comparable to that of Ciclosporin (also called Cyclosporin A).
  • Cyclolinopeptide A is to be used in medi ⁇ caments for immunosuppressive treatment of mammals, including man, for all indications where immunosuppressive treatment is warranted.
  • immunosuppressive treatment is warranted is for the prevention of allograft rejection after organ transplantation and bone marrow transplantation, prophylactic or therapeutic treatment of graft-versus-host-disease (GVDH), and autoimmune diseases, such as acquired immunodeficiency syndrome (AIDS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and diabetes mellitus.
  • GVDH graft-versus-host-disease
  • autoimmune diseases such as acquired immunodeficiency syndrome (AIDS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and diabetes mellitus.
  • AIDS acquired immunodeficiency syndrome
  • SLE systemic lupus erythematosus
  • RA
  • peptide chemistry can be obtained by isolation as described by Kauf ann and Tobschirbel (ibid.), or can be synthesized by any conventional method in the art of peptide chemistry.
  • the a ino acid residues are coupled to each other by known techniques, by using solid phase technique or in solution, forming a linear peptide, which is then cyclized, also in per se known manner by activating the C-terminal and keeping the activated linear peptide in high dilution and low temperature for cyclization.
  • the cyclization is performed e.g. according to the well known azide method.
  • the crude peptide can be purified by crystallization.
  • Fig. 1 shows a graph of post adjuvant polyarthritis in rats treated with CLA.
  • Fig. 2 shows a graph of the effect of CLA on the development of hemolytic anaemia in mice.
  • Fig. 3 shows a graph of the effect of CLA on the survival of mice.
  • the above linear peptide was synthesized by solid phase technique in a Beckman model 9090 peptide synthe- sizer using tert-butoxycarbonyl-protected a ino acids (BocAA) .
  • BocPhe was attached to a chloromethylated resin (1% DVB) by the method of Gisin (Helv. Chim. Acta 5_6_, 1481 (1973)).
  • Boc-Phe-resin was subjected to eight cycles of deprotection (TFA/CH 2 C1 2 ) , neutralization [ (i-Pr) p - EtN/CH 2 Cl 2 ], coupling (BocAA-3 eq. ; DCC-3 eq/CH 2 Cl 2 ), recoupling (BocAA-3 eq. ; DCC-3 eq/CH distractCl 2 ) and termi ⁇ nation ([CH 3 C0] 2 0/CH 2 C1 2 ) performed in a peptide syn ⁇ thesizer.
  • Boc-nonapeptide-resin was deprotected (TFA/CH Stamm- Cl 2 ), neutralized [ (i-Pr) 2 EtN/CH 2 Cl 2 ] and washed (CH 2 Cl 2 ) on-line.
  • the peptide was then cleaved from the resin in its linear form and was transformed to its cyclic form by a suitable procedure in solution.
  • mice were injected intraperitoneally with 0.2 ml of 10% SRBC in PBS 3 hours after the introduction of the reagents. After 4 days, the number of plaqueforming cells (PFC) in the spleen was determined according to
  • Mishell-Dutton (Mishell R.I., Dutton R.W. : J. Exp. Med. , 1967, 126, 423.) The magnitude of the humoral immune response was expressed as the number of PFC per 10 splenocytes. Each group of experimental animals consisted of 7 mice.
  • the number of PFC in each group is expressed as a mean + SE of 7 mice.
  • the number of PFC in each group is expressed as a mean + SE of 7 mice.
  • the number of PFC in each group is expressed as a mean + SE of 7 mice.
  • the number of PFC in each group is expressed as a mean + SE of 7 mice.
  • CBA mice were primed iv with 0.2 ml of 1% SRBC suspension followed by an ip injection of 0.2 ml of 10% SRBC suspension 14 days later.
  • the number of cells in the spleens producing 7S /IgG/ antibodies was deter ⁇ mined 4 days after the second dose of antigen according to Mishell and Dutton (ibid. ) using a rabbit-anti IgG mouse antibodies. The results are depicted in Table 6.
  • mice were injected (primed) intravenously with 0.2 ml of 1% suspension of SRBC in PBS. Four days later, the animals were killed and their spleens were minced, pressed through a plastic screen into 0.83% NH.Cl, buffe ⁇ red with 0.017 M Tris buffer to remove erythrocytes. Then the cells were washed three times with PBS and finally resuspended in RPMI medium supplemented with 10% of fetal calf serum.
  • Solvents DMSO, propylene glycol, PBS Treatment of mice with reagents: The CLA was dissolved in DMSO or in propylene glycol, CS-A was dissolved at desired concentrations in PBS. Mice were treated intraperitoneally or per os with one or with two doses of the reagents, a first dose 3 hours before immunization, second one 48 hours after immuni- zation. As a control an appropriate concentration of the solvent was used.
  • mice DTH was induced in mice according to Lagrange et al (Lagrange P.H. , Mackaness G.B., Miller T.E., Pardon P.: J. Immunol., 1975, 114, 447).
  • Mice were sensitized intravenously with 10 SRBC in 0.1 ml of PBS. After 4 days the reaction was elicited by an intradermal intro- o duction of 10 SRBC into left hind foot pad. The magni- tude of the reaction was measured as the increase of the foot pad thickness at 24 hours following admini ⁇ stration at the challenging dose. The results are means + SE of 7 to 10 mice.
  • mice The results are expressed as a mean + SE of 7 mice.
  • mice Balb/c/Iiw and B_/Iiw mice 8-10 weeks old Reagent: CLA Solvent: DMSO Treatment of mice with CLA:
  • the peptide was dissolved in DMSO, diluted at a desired concentration in PBS and introduced intraperi ⁇ toneally every second day (to the day of rejection) into the animals.
  • DMSO dimethyl methoxysulfoxide
  • Fitted pinch grafts of skin from female Balb/c donor mice were transplanted to female B, recipients according to the method of Billingham and Medawar (Bil- lingham R.E. , Medawar P.B. : J. Expl. Biol. , 1951, 28, 385).
  • Graft survival time was determined by daily obser ⁇ vation.
  • the criterion for rejection being epithelial survival. Results are shown in Table 11.
  • mice CLA was dissolved in an olive oil and CS-A in PBS.
  • the preparations were administered orally 3 times per week beginning the 7th day after transplantation.
  • GvH Graft-versus-host reaction
  • Animals Hybride F, (C3H/Iiw x B g /Iiw) and female B, ice, 8-10 weeks old.
  • Reagents CLA, CS-A.
  • Solvents DMSO, propylene glycol, PBS.
  • mice Treatment of mice with reagents:
  • CLA dissolved in DMSO was introduced into F, (C.-.H x B g ) mice once 3 hours after injecting of parental cells, or twice, the second dose was introduced 48 hours later intraperitoneally.
  • CLA was dissolved in propylene glycol and adminstered into F, (C ⁇ H x B ⁇ ) mice in two doses per os. The first dose 3 hours after introducing parental cells, the second 48 hours later.
  • an appropriate concentration of solvents was used.
  • Preparation of parental cells Female B, mice were killed, their popliteal nodes were pressed through a plastic screen into PBS. Then, the cells were washed three times with PBS and resuspended in RPMI medium: GvH test: GvH reaction was perfomed according to Twist and
  • Hybride mice, F, ( C-.B. x B ⁇ ) were injected subcutaneously in the left hind footpad with 5 x 10 parental lymphoid cells (B). After 7 days, draining lymph nodes were isolated and weighed. As a control, the weight of popliteal node isolated from the right, leg was measured.
  • the intensity of GvH reaction was expressed as a ratio of weights of popliteal lymph nodes isolated from the left and right legs (index of GvH reaction). The results are given in Tables 13 and 14.
  • mice The results are expressed as a mean _+ SE of 7 mice.
  • Polyarthritis was determined by the score at the number of points of inflammatory changes on: legs, tail, nose, ears and eyes. Each group consisted of 10 animals. Results are shown in Fig. 1.
  • mice Blood from mice was collected in citrate saline washed 4 times with PBS and 2% suspension of erythro- cytes was prepared in PBS. Using microtiter plates, samples of mouse erythrocytes were added to diluted
  • CLA suppressed a delayed type hypersensitivity to SRBC in mice, GvH reaction, and prolonged skin graft survival
  • CLA inhibits the development of the disease
  • CLA prolongs the sur ⁇ vival of NZB mice and decreases the incidence of posi ⁇ tive Coombs' test in mice suffering from the disease

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention se rapporte à un cyclolinopeptide A (CLA) représenté par la formule (I) qui est destiné à être utilisé comme agent immunosuppresseur. Sont en outre décrits l'utilisation de cyclolinopeptide A pour la préparation d'un médicament destiné à être utilisé dans un traitement immunosuppresseur, ainsi qu'un procédé de traitement d'un mammifère, y compris l'homme, nécessitant un traitement immunosuppresseur, ce procédé consistant à administrer au mammifère une quantité pharmacologiquement efficace de cyclolinopeptide A. Sont égalements décrits une préparation pharmaceutique comprenant un cyclolinopeptide A, ainsi qu'un ou des véhicule(s), excipient(s) et/ou diluant(s) pharmaceutiquement acceptable(s).
PCT/SE1989/000732 1988-12-23 1989-12-15 Medicament contenant un cyclolinopeptide a Ceased WO1990007523A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019900701862A KR910700263A (ko) 1988-12-23 1989-12-15 시클로리노펩티드를 포함하는 의약

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8804640A SE8804640L (sv) 1988-12-23 1988-12-23 Laekemedel omfattande cyklolinopeptide a
SE8804640-4 1988-12-23

Publications (1)

Publication Number Publication Date
WO1990007523A1 true WO1990007523A1 (fr) 1990-07-12

Family

ID=20374319

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1989/000732 Ceased WO1990007523A1 (fr) 1988-12-23 1989-12-15 Medicament contenant un cyclolinopeptide a

Country Status (5)

Country Link
KR (1) KR910700263A (fr)
AU (1) AU4817790A (fr)
CA (1) CA2006383A1 (fr)
SE (1) SE8804640L (fr)
WO (1) WO1990007523A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005189A1 (fr) * 1990-09-25 1992-04-02 Ferring Ab Analogues de cyclolinopeptide a et leur utilisation
WO2009079792A1 (fr) 2007-12-21 2009-07-02 University Of Saskatchewan Récupérations de peptides hydrophobes à partir d'huiles
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US20140329741A1 (en) * 2011-12-19 2014-11-06 University Of Saskatchewan Use of cyclic peptides from flaxseed for improving animal and human health
WO2019149450A1 (fr) 2018-02-01 2019-08-08 Sederma Utilisation de peptides cycliques dans un produit cosmétique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANGEW. CHEM., Vol. 98, No. 11, 1986, VON HORST KESSLER et al.: "Konformative Voraussetzungen fuer die in-vitro-Inhibierung der Cholataufnahme in Hepatocyten durch cyclische Antamanid- und Somatostatin-Analoga", see page 1030-page 1032. *
BIOCHIMICA ET BIOPHYSICA ACTA, Vol. 860, 1986, KLAUS MUENTER et al.: "Characterization of a transporting system in rat hepatocytes. Studies with competitive and non-competitive inhibitors of phalloidin transport", see page 91-page 98. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005189A1 (fr) * 1990-09-25 1992-04-02 Ferring Ab Analogues de cyclolinopeptide a et leur utilisation
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2009079792A1 (fr) 2007-12-21 2009-07-02 University Of Saskatchewan Récupérations de peptides hydrophobes à partir d'huiles
CN101945888A (zh) * 2007-12-21 2011-01-12 萨斯喀彻温大学 从油回收疏水性肽
US8383172B2 (en) 2007-12-21 2013-02-26 University Of Saskatchewan Recovery of hydrophobic peptides from oils
US20140329741A1 (en) * 2011-12-19 2014-11-06 University Of Saskatchewan Use of cyclic peptides from flaxseed for improving animal and human health
US20170095527A1 (en) * 2011-12-19 2017-04-06 University Of Saskatchewan Use of cyclic peptides from flaxseed for improving animal and human health
WO2019149450A1 (fr) 2018-02-01 2019-08-08 Sederma Utilisation de peptides cycliques dans un produit cosmétique

Also Published As

Publication number Publication date
SE8804640D0 (sv) 1988-12-23
KR910700263A (ko) 1991-03-14
CA2006383A1 (fr) 1990-06-23
SE8804640L (sv) 1990-06-24
AU4817790A (en) 1990-08-01

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