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WO1994006453A1 - Antagonistes de la bradykinine contenant des acides amines aliphatiques en position 5 - Google Patents

Antagonistes de la bradykinine contenant des acides amines aliphatiques en position 5 Download PDF

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Publication number
WO1994006453A1
WO1994006453A1 PCT/US1993/008220 US9308220W WO9406453A1 WO 1994006453 A1 WO1994006453 A1 WO 1994006453A1 US 9308220 W US9308220 W US 9308220W WO 9406453 A1 WO9406453 A1 WO 9406453A1
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WO
WIPO (PCT)
Prior art keywords
arg
bradykinin
aliphatic
pro
cpg
Prior art date
Application number
PCT/US1993/008220
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English (en)
Inventor
John M. Stewart
Lajos Gera
Ved Srivastava
Original Assignee
Stewart John M
Lajos Gera
Ved Srivastava
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 Stewart John M, Lajos Gera, Ved Srivastava filed Critical Stewart John M
Priority to AU50985/93A priority Critical patent/AU5098593A/en
Publication of WO1994006453A1 publication Critical patent/WO1994006453A1/fr

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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
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/18—Kallidins; Bradykinins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to novel biologically active peptides which act as antagonists of the biological activities of bradykinin and its homologs and congeners, their pharmaceutically acceptable salts, and their application as therapeutic agents. More particularly, the invention pertains to modified bradykinin antagonist peptides that do not contain any aromatic amino acids or at least no aromatic residue in the 5-position and preferably also none in the 7- and 8-positions. Heretofore, all bradykinin antagonist peptides have had an aromatic or substituted aromatic amino acid residue at the position analogous to that of position 5 of bradykinin.
  • the bradykinin antagonist peptides of the present invention contain aliphatic, alicyclic, aliphatic heterocyclic or substituted alicyclic or aliphatic heterocyclic amino acid residues at that position.
  • Bradykinin (usually abbreviated BK) has the amino acid sequence:
  • bradykinin Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (BK) position : 1 2 3 4 5 6 7 8 9
  • Lys-BK also called kallidin
  • Met-Lys-BK Met-Lys-BK.
  • humans also produce the analog in which the 3-proline is replaced by trans- 4-hydroxyproline.
  • Bradykinin and its physiologically important related peptides kallidin (Lys-bradykinin) and Met-Lys-bradykinin, exhibit physiological actions which qualify them as mediators of inflammatory reactions, hypotensive states, and pain. Bradykinin is overproduced in pathological conditions such as septic shock (Robinson et al. , Am. J. Med.. 5_9.:61, 1975) and hemorrhagic (Hirsch et al . , J. Surg. Res. , 37:147, 1974), anaphylaxis
  • bradykinin The production of bradykinin from the plasma results in pain at the site of the pathological condition, and the overproduction intensifies the pain directly or via stimulation by bradykinin of the activation of the arachidonic acid pathway which produces prostaglandins and leukotrienes, the more distal and actual mediators of inflammation.
  • Literature references describing these actions of bradykinin and related peptides are found in Handbook of Experimental Pharmacology, Vol. 25, Springer-Verlag, 1970 and VOl . 25 Supplement, 1979 and in Stewart, in "Mediators of the Inflammatory Process", Henson and Murphy, eds. , Elsevier, 1989.
  • Bradykinin as discussed, has been found to be produced in inflammatory reactions in the intestine provoking contraction of smooth muscle and secretion of fluid and ions.
  • the existence of specific bradykinin receptors in the mucosal lining of the intestine and intestinal smooth muscle is demonstrated by Manning et al . in Nature (229 :256- 259, 1982) showing the influence of bradykinin in very low concentrations upon fluid and ion secretion.
  • bradykinin and associated pain in angina has been studied and reported by Kimura et al . in American Heart Journal ( 5.:635-647, 1973) and by Staszewska-Barczak et al. in Cardiovascular Research ( ⁇ j) :314-327, 1976) .
  • the reported action of bradykinin and prostaglandins acting in concert are the natural stimulus for excitation of the sensory receptors signalling the pain of myocardial ischaemia.
  • Bradykinin and bradykinin-related kinins are not only produced by the animal but may also be injected as a result of stings and bites. It is known that insects such as hornets and wasps inject bradykinin related peptides which also cause pain, swelling and inflammation.
  • bradykinin which is essential for the development of useful tools for diagnostic use, and for the development of therapeutic agents aimed at alleviating the intense pain and other symptoms caused by the production and overproduction of bradykinin, was severely hindered by the lack of specific sequence-related competitive antagonists of bradykinin until the discovery of the first effective bradykinin antagonists by Vavrek and Stewart in 1985. (Peptides. £.161-164, 1985; U.S. Patent 4,693,993, September 15, 1987) .
  • bradykinin In all those peptide antagonists of bradykinin, the proline residue at position 7 of bradykinin was replaced by a D-aromatic acid residue, usually D-phenylalanine or D-thienylalanine.
  • a D-aromatic acid residue usually D-phenylalanine or D-thienylalanine.
  • many modifications of the original bradykinin antagonists have been described, but all effective antagonists have had an aromatic amino acid residue at position 5 and a D-aromatic residue at position 7.
  • the residue at position 8 was usually an aromatic amino acid, although in certain antagonists, the 5-7-8 arrangement was aromatic-D-aromatic-aliphatic. More recently, effective bradykinin antagonists have been described in which the 5-7-8 arrangement is aromatic-D-aliphatic-aliphatic (R.J. Vavrek and J.M. Stewart in "Kinins 1991", H. Fritz, ed. , Agents and Actions Supplement, 1992; D.J. Kyle et al., J. Med. Chem.. 34_:2649-2653, 1991) .
  • the prior art has not described effective bradykinin antagonists having the 5-7-8 arrangement of aliphatic-D-aliphatic-aliphatic or aliphatic, D- aromatic, aliphatic. Effective, potent bradykinin antagonists having this type of structure are the subject of this invention.
  • the structures of effective bradykinin antagonist peptides described in the prior art can be summarized as follows:
  • bradykinin antagonists are also known in which other residues are used, such as:
  • This invention relates to modification of the structures of known bradykinin antagonist peptides to replace the aromatic amino acid residue at position 5 of the bradykinin antagonist structure with an aliphatic, alicyclic, or substituted alicyclic amino acid residue.
  • bradykinin analogs were previously synthesized as potential antagonists having an aliphatic amino acid residue at position 5, but always in combination with a position 7-8 substitution that was
  • bradykinin antagonist peptides of the present invention may be characterized by Formula 3 :
  • Formula 3 X--A--B--C--D--E--F--G--H--J--K--Z position number 0 1 2 3 4 5 6 7 8 9
  • X is an aromatic, aliphatic, or urethane-type acylating group, a single amino acid of the D- or L- configuration, or a di- or poly-peptide containing amino acids of the D- or L- configuration, or a combination of these
  • A is D-Arg or another basic or neutral aromatic, aliphatic, heterocyclic or alicyclic amino acid of the D- or L- configuration
  • B is Arg or another basic or neutral aromatic, aliphatic, heterocyclic or alicyclic amino acid of the D- or L- configuration
  • C is Pro, Hyp, or another basic or neutral aromatic, aliphatic, heterocyclic, or alicyclic amino acid of the D- or L- configuration
  • D is Pro, Hyp, or another basic or neutral aromatic, aliphatic, heterocyclic, or alicyclic amino acid of the D- or L- configuration
  • E is Gly or another basic or neutral aromatic, aliphatic, heterocyclic, or alicyclic amino acid of the D- or L- configuration
  • F is Cpg or another aliphatic, aliphatic heterocyclic, or alicyclic amino acid of the D- or L- configuration
  • G is preferably Ser or Cys of the D- or L- configuration or another aromatic, aliphatic, heterocyclic, or alicyclic amino acid of the D- or L- configuration
  • H is D-Cpg or another aliphatic, aliphatic heterocyclic, or alicyclic amino acid of the
  • J is Cpg or another aliphatic, aliphatic heterocyclic, or alicyclic amino acid of the D- or L- configuration
  • K is Arg or another basic or neutral aromatic, aliphatic, heterocyclic or alicyclic amino acid of the D- or L- configuration
  • Z is the carboxy-terminal carboxyl group or a carboxy-terminal extension composed of an amino acid of the D- or L-configuration or a peptide composed of amino acids of the D- or L-configuration.
  • Salts of bradykinin antagonist peptides of Formula 3 include salts with HCl, TFA, HOAc, as well as other pharmaceutically acceptable salts. Suitable substitutions in the various positions of all-aliphatic bradykinin antagonists peptides of Formula 3 may be represented as follows (alignment of the residues in a particular row does not imply nor limit to a given peptide sequence) :
  • bradykinin antagonist peptides of the present invention may be more exactly represented by Formula 4 :
  • a preferred compound of Formula 4 is the following peptide:
  • bradykinin antagonist peptides of the present invention by SPPS may be carried out manually (see Stewart & Young) or by use of the Beckman Model 990, Biosearch Model 9500 or other automatic peptide synthesizers, and involves use of standard procedures, defined as follows:
  • PROCEDURE A DCC coupling reaction:
  • PROCEDURE B DIC coupling:
  • PROCEDURE D TFA deprotection and neutralization: (Stewart & Young p. 76) .
  • the deprotection reagent is TFA:DCM (1:3) , containing 1 mg/ml indole. It is used for 30 minutes, following a prewash.
  • the neutralization reagent is 10% TEA in DCM, prepared fresh and used twice for one minute.
  • PROCEDURE F HF cleavage and deblocking: (Stewart & Young p. 85) .
  • PROCEDURE G PURIFICATION OF PEPTIDES:
  • the peptides may be purified by CCD for 100 transfers in the appropriate system, as determined by preliminary k estimation:
  • Chlorine-tolidine and Sakaguchi spray reagents may be used.
  • PROCEDURE J Paper electrophoresis (ELEC) :
  • ELEC may be done in buffers of pH 2.8 and 5.0 as described in Stewart & Young. Chlorine-tolidine and Sakaguchi spray reagents may be used.
  • Preparative HPLC may be carried out on large-pore reversed phase C4 or C8 columns in a gradient of 0.1% TFA in H20 to 0.08% TFA in acetonitrile. Detection may be by UV at 214 nm. Analytical HPLC may be carried out in the same system and in a gradient of acetonitrile in 0.25M triethylammonium phosphate, pH 6.5.
  • PROCEDURE L MASS spectroscopy
  • Peptides may be checked for- the correct molecular mass by FAB mass spectroscopy.
  • PROCEDURE M Amino acid analysis (AAA) :
  • Peptides may be hydrolyzed in 6N HCl and analyzed as described in Stewart &. Young, pp. 109-
  • the 990 synthesizer vessel is loaded with 1.66g of Boc-Arg(Tos) -OHMR (0.24 mmol/g substitution; 0.4 mmol total) .
  • Boc-L-Cpg is coupled by Procedure C. Coupling is checked for completeness with the Kaiser test, and is repeated if necessary.
  • Boc-D-Cpg and Boc-Ser(Bzl) are next coupled in order using Procedure C.
  • the peptide-resin is divided into 4 parts, and synthesis was continued on the 0.1 mmol scale, using BOP procedure C. The peptide-resin is deprotected by Procedure E and dried.
  • the peptide is cleaved from the resin and deblocked by Procedure F.
  • the peptide is purified by CCD using Procedure G and System A.
  • the purified peptide is checked for purity by TLC (Procedure H) , ELEC (Procedure I) and HPLC (Procedure K) , and characterized by AAA (Procedure M) and MASS (Procedure L) .
  • TLC Process H
  • ELEC Protectedure I
  • HPLC Procedure K
  • AAA Procedure M
  • MASS Procedure L
  • bradykinin antagonists are assayed on isolated rat uterus in natural or induced estrus and on guinea pig ileum, according to the commonly accepted assay methods for bradykinin and related kinins as described by Trautschold (Handbook of Expt. Pharmacol., Vol. 25, Springer Verlag, pp. 53- 55, 1969) for inhibition of the myotropic activity of bradykinin.
  • the inhibition potencies are determined according to the commonly accepted manner described by Schild for antagonists of biologically active compounds (Br. J. Pharmacol.. 2..189, 1947), and expressed as pA values. In the assays, a dose- response curve is determined for the reference substance bradykinin.
  • the dose of bradykinin which produces a half-maximal contraction of tissue is the ED dose.
  • An amount of bradykinin equivalent to twice the ED dose is administered to the tissue 30 seconds after the start of incubation of the tissue with a dose of antagonist.
  • Doses of antagonist are increased in the protocol until the dose of antagonist is found that causes the tissue response to a double ED 50 dose of bradykinin in the presence of antagonist to equal the response of an EDb_ n (J dose of bradykinin without antagonist.
  • the pA value represents the negative logarithm of the molar concentration of antagonist necessary to reduce the response of a double ED dose of bradykinin to that of an ED dose without antagonist.
  • a change of one unit of pA value represents an order of magnitude change in potency.
  • the negative log of the dose of BK that half-maximal contraction of the tissues, is commonly known as the pD value.
  • the pD value for bradykinin is 7.9 on the rat uterus and 7.4 on the guinea pig ileum.
  • bradykinin antagonists The m vivo effects of bradykinin antagonists on blood pressure in the anesthetized rat are determined according to the assay described by Roblero, Ryan and Stewart (Res. Commun. Pathol. Pharmacol. , 6.:207, 1973) .
  • the antagonists produce inhibition of the bradykinin response when injected as a bolus admixture of bradykinin plus antagonist by either the ia or iv route of administration, or when administered as an infusion. Potencies for the antagonist in this assay are not reported quantitatively but rather are indicated qualitatively. The results of tests on compounds of the various Examples are reported in Table I.
  • Antagonist potency is given as percent of BK potency.
  • Antagonist potency is given as pA foi and is underlined.
  • blood pressure assay ⁇ indicates unquantitated antagonist potency.
  • the antagonists of the invention may be used in the form of conventional pharmaceutical compositions comprising the antagonist and a pharmaceutically acceptable carrier. Such compositions may be adapted for topical, oral, aerosolized, intramuscular, subcutaneous or intravenous administration.
  • the amount of antagonist present in such compositions will range from, for example, about 0.001 to 90.0% by weight depending on the application and mode of administration although more or less of the active component may be used.
  • Conventional dosages will vary considerably on the basis of the intended application and mode of administration, e.g. 0.1 to 100 micrograms per kg body weight per minute are contemplated for use in the context of the septic shock.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention se rapporte à des peptides antagonistes de la bradykinine qui ont un résidu hétérocyclique aliphatique, alicyclique ou aliphatique en position 5 et de préférence en positions 7 et 8.
PCT/US1993/008220 1992-09-11 1993-09-08 Antagonistes de la bradykinine contenant des acides amines aliphatiques en position 5 WO1994006453A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50985/93A AU5098593A (en) 1992-09-11 1993-09-08 Bradykinin antagonists containing aliphatic amino acids in the 5-position

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94231792A 1992-09-11 1992-09-11
US07/942,317 1992-09-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2739553A1 (fr) * 1995-10-06 1997-04-11 Oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
EP0836853A1 (fr) * 1996-10-14 1998-04-22 Hoechst Aktiengesellschaft Utilisation des antagonistes de bradykinin pour la fabrication d'un médicament pour le traitement de la maladie d'Alzheimer
US5834431A (en) * 1995-09-08 1998-11-10 Cortech, Inc. Des-Arg9 -BK antagonists
US5863901A (en) * 1996-03-27 1999-01-26 Hoechst Aktiengesellschaft Use of bradykinin antagonists for the production of pharmaceuticals for the treatment of chronic fibrogenetic liver disorders and acute liver disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4693993A (en) * 1985-06-13 1987-09-15 Stewart John M Bradykinin antagonist peptides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4693993A (en) * 1985-06-13 1987-09-15 Stewart John M Bradykinin antagonist peptides

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5834431A (en) * 1995-09-08 1998-11-10 Cortech, Inc. Des-Arg9 -BK antagonists
FR2739553A1 (fr) * 1995-10-06 1997-04-11 Oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
WO1997013493A1 (fr) * 1995-10-06 1997-04-17 L'oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
US6468972B1 (en) 1995-10-06 2002-10-22 Societe L'oreal S.A. Method to promote, stimulate and/or delay hair loss by a brady kinin antagonist
US5863901A (en) * 1996-03-27 1999-01-26 Hoechst Aktiengesellschaft Use of bradykinin antagonists for the production of pharmaceuticals for the treatment of chronic fibrogenetic liver disorders and acute liver disorders
EP0836853A1 (fr) * 1996-10-14 1998-04-22 Hoechst Aktiengesellschaft Utilisation des antagonistes de bradykinin pour la fabrication d'un médicament pour le traitement de la maladie d'Alzheimer
US6245736B1 (en) 1996-10-14 2001-06-12 Aventis Pharma Deutschland Gmbh Use of peptidic bradykinin antagonists for the treatment and prevention of Alzheimer's disease

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AU5098593A (en) 1994-04-12

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