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EP0332688A1 - Peptides antagonistes de bradykinine - Google Patents

Peptides antagonistes de bradykinine

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Publication number
EP0332688A1
EP0332688A1 EP88908552A EP88908552A EP0332688A1 EP 0332688 A1 EP0332688 A1 EP 0332688A1 EP 88908552 A EP88908552 A EP 88908552A EP 88908552 A EP88908552 A EP 88908552A EP 0332688 A1 EP0332688 A1 EP 0332688A1
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EP
European Patent Office
Prior art keywords
phe
bradykinin
arg
substituted
effective amount
Prior art date
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EP88908552A
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German (de)
English (en)
Other versions
EP0332688A4 (en
Inventor
John M. Stewart
Raymond J. Vavrek
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Individual
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Individual
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Publication of EP0332688A1 publication Critical patent/EP0332688A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention pertains to new and useful bradykinin antagonist peptides and is related to the subject matter of U.S. Application Serial No. 091.995 filed concurrently herewith.
  • the invention relates to novel biologically active peptides which act as antagonists of the biological activities of bradykinin, their pharmaceutically acceptable salts, and their application as therapeutic agents. More particularly the invention pertains to bradykinin antagonists having a critical 7 position substitution and lacking an alpha amino group or having a beta amino acid residue alone or together with sequence deletions and with or without an aromatic amino acid residue at position nine.
  • bradykinin In the 25 years since the sequence of the potent mammalian vasodilator peptide bradykinin was described and synthesized (Boissonnas et al., Experientia 16:326, 1960) several hundred sequence-related peptide analogs have been synthesized and assayed in biological systems (Schroeder, in Handbook of Experimental Pharmacology, Vol. 25, (Springer Verlag) pp. 324-350, 1970) (Stewart, Handbook of Experimental Pharmacology, Vol. 25 (Supplement), (Springer Verlag pp.227-272, 1979). The objective in these studies was to investigate the varied physiological and pharmacological roles of bradykinin.
  • 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. 59: 61, 1975) and hemorrhagic (Hirsch et al., J. Surg. Res. 17:147, 1974) anaphylaxis (Collier and James, J. Physiol. 160:15P. 1966), arthritis (Jasani et al., Am. Rheum. Dis.
  • pathological conditions such as septic shock (Robinson et al., Am. J. Med. 59: 61, 1975) and hemorrhagic (Hirsch et al., J. Surg. Res. 17:147, 1974) anaphylaxis (Collier
  • bradykinin inflammatory bowel disease
  • certain other conditions including acute pancreatitis, post-gastrectomy dumping syndrome, carcinoid syndrome, migraine, and angioneurotic edema
  • 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.
  • 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 (85:635-647, 1973) and by Staszewska - Barczak, et al in Cardiovascular Research (10:314-327, 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 ischemia.
  • 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 caused by the production and overproduction of bradykinin, has been severely hindered by the lack of specific sequence-related competitive antagonists of bradykinin.
  • bradykinin Several non-peptide, non-specific and non-selective antagonists of one or more of the biological activities of bradykinin have been described among compounds as diverse as analgesics and anti-inflammatory substances, which act via the prostaglandin system and not directly on bradykinin biological receptors (Rocha e Silva and Leme, Med. Exp, 8:287, 1963). These are antihistamines (Geese et al, J. Pharm. Pharmacol. 21: 544, 1969); bradykinin-antibodies (Grez et al, Eu. J. Pharmacol. 29:35, 1974); benzodiazepine derivatives (Leme and Rocha e Silva, Br. J. Pharmacol.
  • bradykinin 25:50, 1965; high molecular weight ethylene oxide polymers (Wilkens and Back, Arch. Intl. Pharmacodynam. 209:305, 1974); gallic acid esters (Posati et al., J. Agri. Food Chem. 18:632, 1970) and serotonin inhibitors (Gomazkon and Shimkovich, Bull. Exptl. Biol. Med. 80:6, 1975). None of these individual compounds or classes of compounds specifically inhibit bradykinin.
  • Heptyl esters of various amino acid-containing substances such as single basic amino acids (ie. Arg and Lys) (Geese, Adv. Exptl. Biol. Med. 70:5, 1976), the dipeptide Phe-Gly (Geese et al. Int. Aech. Allergy 41:174, 1971), and of analogs of C- terminal peptide fragments of bradykinin (ie, Pro-Phe-Arg) (Claesson et al., Adv. Exptl. Med. Biol. 120B: 691, 1979) have been reported as anti-bradykinin substances. When tested in bradykinin assay systems they prove to be weak partial agonists/antagonists, depending on the dose, with little specificity for inhibiting bradykinin action.
  • bradykinin analogs containing the O-methyl ether of Tyr residues at positions 5 and/or 8 have been reported to produce mixed agonist/antagonist activity on isolated uteri of galactosemic rats, but not on normal rats.
  • the antagonism was not reliably reproducible in these animals (Stewart and Woolley, in Hypotensive Peptides, Springer Verlag, pp. 23-33, 1966).
  • bradykinin in the systemic circulation is less than 30 seconds (S.H. Ferreira & J.R. Vane, Br. J. Pharmacol. Chemotherap. 30:417, 1967). Bradykinin is completely destroyed (98-99% destruction) on a single passage through the pulmonary circulation (J. Roblero, J.W. Ryan and J.M. Stewart, Res. Commun. Pathol. Pharmacol. 6:207, 1973) as determined in the anesthetized rat by measuring the depressor effects of an agonist following intra-aortic (IA) (bypassing the pulmonary circulation) and intravenous (IV) administration.
  • IA intra-aortic
  • IV intravenous
  • bradykinin agonists to pulmonary kininase destruction in vivo is promoted by addition of single (ie, DArg-, DLys-, Lys-) and double (DLys-Lys-) basic amino acid residues to the N-terminal of the bradykinin sequence.
  • the addition of the dipeptide Lys-Lys to the N-terminal of bradykinin agonists confers complete resistance to in vivo destruction on initial passage through the pulmonary circulation (Roblero, Ryan and Stewart, Res. Comm. Pathol. Pharmacol . 6 : 207 , 1973 ) .
  • the invention relates to the modification of the sequence of the mammalian peptide hormone bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and pharmaceutically acceptable salts thereof, at the Pro residue at position 7 in a unique manner which, produces sequence-related analogues that act as specific and competitive inhibitors of the biological activities of bradykinin.
  • the invention specifically relates to the substitution of the L-Pro at position 7 with substituted and unsubstituted aromatic amino acids of the D-configuration, a change which converts bradykinin agonists into antagonists, and includes additional modifications at other positions within the 7-position modified bradykinin antagonist which confer increased antagonist potency, resistance to enzymatic degradation and/or tissue specificity on the D-amino acid-containing bradykinin sequence.
  • the invention further includes the necessary substitution of L-Pro at position 7 with substituted and unsubstituted amino acids of the D configuration together with the substitution of arginine in the one and nine positions with D or L-cyclic (heterocyclic or alicyclic), aliphatic amino acid residue.
  • the invention also includes the necessary substitution of L-Pro at position seven to provide bradykinin antagonists lacking an alpha amino group or having a beta amino acid residue alone or together with sequence deletions or terminal extensions. More specifically, the invention relates to the peptides of the general formula: Formula I
  • N is a hydrogen atom or single acidic, basic, neutral or aromatic amino acid residue of the D- or L- configuration, such as D-Arg, D-Lys or L-Thi, an N-terminal enzyme protecting group from the group comprising acyl-type protecting groups, ⁇ irethane-type protecting groups, alkyl-type protecting groups, or alternately N is a di- or poly-peptide containing amino acids of the D- or L- configuration, such as Lys-Lys, Met-Lys, or Gly-Arg-Met-Lys;
  • A1 lacks an alpha amino group or A1 and A9 are either or both an Arg residue or other cyclic (heterocyclic or alicyclic) amino acid residue, aliphatic amino acid residue or an aromatic or substituted aromatic amino acid residue of the D or L configuration;
  • B is D- or L-Pro residue, or other D- or L-cyclic (hetero or alicyclic) or noncyclic aliphatic amino acid residue, such as L-hydroxyproline, or a substituted or unsubstituted beta amino acid residue of the D- or L-configuration or a D- or L-aromatic or substituted aromatic amino acid residue or wherein B is deleted;
  • C is D- or L-Pro residue, or other cyclic (heterocyclie or alicyclic), aliphatic, aromatic or substituted aromatic amino acid residue of the D- or L-configuration or wherein C is deleted;
  • D is a Gly residue or other aliphatic, aromatic or substituted aromatic amino acid residue of the D- or L-configuration, such as Ala, or wherein D is deleted;
  • W is a Phe residue of the L-configuration, or a substituted Phe or other aliphatic or aromatic amino acid residue of the D or L configuration, such as Leu, beta-2-thienyl-alanine (Thi) or 2-pyridyl-alanine (Pal);
  • X is a Ser residue of the D- or L-configuration, a Gly residue, or other aliphatic, cyclic, aromatic or substituted aromatic amino acid residue of the D- or L-configuration, such as pCl-D-Phe or D-Phe;
  • Y is a D-aromatic amino acid residue, or substituted aromatic amino acid residue, such as D-Phe, beta-(2-thienyl)-D Ala (DThi), beta-(2-pyridyl)-D-Ala (D-Pal), ⁇ -2-naphthyl-D Ala (D-Nal), DHis, D-homo-Phe (DhPhe), O-methyl-DTyr (DOMT), D-alphaphenyl-Gly (DPhg), DTrp, DTyr or pCl-DPhe (CDF);
  • D-Phe beta-(2-thienyl)-D Ala
  • DThi beta-(2-pyridyl)-D-Ala
  • D-Nal ⁇ -2-naphthyl-D Ala
  • DHis D-homo-Phe (DhPhe), O-methyl-DTyr (DOMT), D-alphaphenyl-Gly (
  • Z is a Phe residue of the L-configuration, or a substituted Phe or other aliphatic or aromatic amino acid residue of the D- or L-configuration, such as Leu, Thi or Pal or a cyclic amino acid such as a D- or L-Pro.
  • Salts of peptides of general formula I include salts with HCl, TFA, AcOH, as well as other pharmaceutically acceptable salts.
  • the resin was air dried to constant weight to give 18.5 gm of Boc-Arg(Tos) -hydroxymethyl-resin, with an actual amino acid content of 0.272 millimoles of Arg per g of resin as determined by quantitative amino acid analysis of a sample of the amino acid resin following hydrolysis (4 hr, 130 degrees C) in 6 N HCL/propionic acid.
  • the resin 1.5 gm containing a total of 0.4 mMole of Arg, was placed in the reaction vessel of an automatic solid-phase synthesizer (Beckman model 990) and subjected to one cycle of addition for the coupling of Boc-Phe as follows;
  • PROGRAM A STANDARD DCC COUPLING:
  • the resin was washed three times with 20ml portions of DCM.
  • the resin was then equilibrated with 20ml of a 1:3 ratio of trifluoroacetic acid (TFA) in DCM containing 0.1% indole for 1.5 minutes. The equilibration was then repeated for 30 minutes.
  • the resin was then washed six times with 20ml portions of DCM followed by neutralization with a 10% solution of (Et 3 N) in DCM for one and one half minutes, then the neutralization step was repeated.
  • the resin was washed six times with 20ml of DCM and then equilibrated with a solution of 1.0 mMole of Boc-Phe in DCM for one and one half minutes. Then four ml of 0.25 N DCC in DCM was added and the mixture stirred for two hours. Then the resin was washed three times with 20ml portions of DCM.
  • the N-Terminal protecting group was removed according to the following sequence:
  • PROGRAM D. RECOUPLE
  • the peptide-resin salt was first washed three times with 20ml portion of DCM, then neutralized with 10% Et 3 N DCM for 1.5 minutes. The neutralization step was then repeated and the peptide-resin-salt was washed six times with 20ml portions of DCM. The peptide-resin was then equilibrated with a solution of 1.0 mMole of Boc-Ser(OBzl) in DMF for 1.5 minutes. Four ml of 0.25 N DCC in DCM was added and mixed with the resin for two hours. The product was washed three times with DCM.
  • the peptide was purified by countercurrent distribution (CCD) (100 upper phase transfers in a Post CCD apparatus) in the solvent system nBuOH:1% TFA (1:1). The content of the tubes corresponding to the main peptide- containing peak, as determined by the quantitative Sakaguchi reagent, was collected, the solvent evaporated under reduced pressure, the residue dissolved in glacial acetic acid (AcOH) and lyophilized to give 140 mg of peptide with a partition coefficient (k) from the CCD of 5.7.
  • Examples 2 - 4 of the invention relate to novel modifications of the bradykinin (BK) sequence (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in which the N-terminal of BK antagonist sequences are modified by removal of the alpha-amino group and include a D amino acid at position 7..
  • BK bradykinin
  • Such modified BK analogs referred to as desamino-antagonists, exhibit antagonism of BK-induced pharmacological responses, and represent a new class of BK-related peptide antagonists.
  • desamino-BK possesses about 20% of BK agonist potency on smooth muscle.
  • Examples 2 - 4 represent bradykinin antagonists lacking an alpha amino group and containing a D-hydrophobic amino acid residue at position seven with or without a sequence deletion at other positions in the bradykinin antagonist which were prepared by methods similar to those described in Example 1.
  • Examples 5 - 8 represent bradykinin antagonist containing beta amino acid residues with a D-hydrophobic amino acid residue at position 7 with or without a sequence deletion at other positions in the bradykinin antagonist which were prepared by methods similar to those described in Example 1.
  • Examples 9 - 19 represent deletion analogs of bradykinin antagonist peptides possessing bradykinin antagonist activity which were prepared by methods similar to those described in Example 1.
  • k(415) 0.235, Arg - 2.13, Gly - 1.05, Phe - 3.02, Ser - 0.93, Hyp - 0.87.
  • Arg-Gly-Phe-Ser-DPhe-Phe-Arg [(des-Pro 2,3 )-DPhe 7 -BK)]: k(1.1) 5.250, Arg - 2.14, Gly - 1.00, Phe - 2.93, Ser - 0.93.
  • k(415) 0.515, Arg - 2.09, Gly - 1.02, Ser - 0.99,
  • k(415) 0.961, Arg - 2.35, Gly - 1.20, Phe - 3.96, Ser - 0.83.
  • Examples 20 - 23 of the invention relate to novel modifications of the bradykinin (BK) sequence (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) having the critical 7 position substitution in which the C-terminal arginine residue of BK antagonist sequence is replaced by an aromatic amino acid residue, and in addition an amino acid residue is deleted within the sequence.
  • BK bradykinin
  • Such modified BK analogs exhibit antagonism of BK-induced pharmacological responses and represents a new class of BK-related peptide antagonists.
  • the present modifications of BK antagonist sequences represent novel BK antagonists with biological and therapeutic potential.
  • Examples 20 - 23 represent bradykinin antagonist peptides possessing a C-terminal phenylalanine (Phe).
  • Peptide analogs possessing a C-terminal Phe residue are prepared by methods described in the Example 1 for the preparation of
  • Examples 20 - 23 represent bradykinin antagonist peptides possessing an aromatic amino acid residue at position nine in place of arginine and sequence deletions.
  • the bradykinin antagonist peptides were prepared by methods similar to those described for Example 1.
  • bradykinin antagonists were 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, 1970) for inhibition of the myotropic activity of bradykinin.
  • the inhibition potencies as 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 2 values are determined on isolated rat uterus (RUT) and isolated guinea pig ileum (GPI).
  • a dose-response curve is determined for the reference substance bradykinin.
  • the dose of bradykinin which produced a half maximal contraction of tissue is the ED 50 dose.
  • An amount of bradykinin equivalent to twice the ED 50 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 this protocol until pre-incubation with a dose of antagonist reduces the contraction in response to the double ED 50 dose of bradykinin to response of a single ED 50 dose of bradykinin.
  • the pA 2 value represents the negative logarithm of the molar concentration of antagonist necessary to reduce the response of a double ED 50 dose of bradykinin to that of an
  • ED 50 dose One unit of pA 2 value represents an order of magnitude change in potency.
  • the negative log of the dose of BK the dose which causes half maximal contraction of the tissues, is commonly known as the pD 2 value.
  • the pD 2 value for bradykinin is 7.9 on the rat uterus and 7.4 on the guinea pig ileum.
  • the values for compounds of various Examples are reported in Table IV.
  • Biological activity is listed for the analogs on rat uterus (RUT), and guinea pig ileum (GPI).
  • Agonist potency is listed as percent of BK potency.
  • Antagonist potency is listed as the pA 2 value and is underlined, followed in parentheses by the number of tissues in the determination. I/O indicates analog exhibits both antagonism and no effect on separate tissues in screening assays.
  • bradykinin antagonists of this invention are demonstrated by their ability to inhibit the myotropic activity of bradykinin (BK) and two physiologically important BK-related kinins, kallidin (KAL, Lys-BK) and methionyl-lysyl-BK (MK-BK), but not the myotropic activity induced by non kinin-related peptides, such as angiotensin-II (ANG) or substance-P (SP).
  • BK-related antagonists inhibited contractions produced by BK-related agonists, but had no effect on the non-kinin myotropic peptide substances.
  • the inhibition potencies are listed as pA2 values as described above in Table IV.
  • bradykinin antagonists The in 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 also 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.
  • the results of tests on compounds of various Examples are reported in Table V.
  • Biological activity is listed for the analogs on rat blood pressure (RBP) following intra-aortic (IA) and intravenous (IV) bolus administration.
  • I(P) indicates partial antagonism.
  • I/O indicates analog exhibits both antagonism and no effect on separate animals.
  • 1(B) indicates antagonism of BK-induced depressor effect.
  • PRS indicates pressor effect.
  • bradykinin antagonists include not only treatment for the production of bradykinin or related kinins by the animal but also the injection of bradykinin related peptides into an animal as a result of bites and stings.
  • Topical application alone or in combination with subcutaneous utilization of the bradykinin antagonists of the invention can be employed to treat the effects of bradykinin-related peptides causing pain, inflammation and swelling.
  • bradykinin antagonists of this invention for other traumatic, inflammatory or pathological conditions which are known to be mediated by bradykinin or exacerbated by an overproduction of bradykinin can also be achieved. These conditions include local trauma such as wounds, burns and rashes, angina, arthritis, asthma, allergies, rhinitis, shock, inflammatory bowel disease, low blood pressure, systemic treatment of pain and inflammation, and low sperm motility which produces male infertility.
  • the present bradykinin antagonists, as discussed may be advantageously administered in a variety of ways including sublingual absorption as with nitroglycerine or patch administration using agents for assisting absorption through the skin such as for the treatment of angina. Based upon the PA 2 and ED 50 data disclosed in this invention and in the prior art related to agonist potency, it is possible for one skilled in the art to make a determination of the dosage of the novel bradykinin antagonists of the invention.
  • the dosage range for typical application in such conditions as the pain and inflammation of wounds, burns and rashes would be 0.1 - 5mg/ml; for a nasal spray formulation suitable for treating rhinitis, allergies and asthma suitable dosage range would be 0.1 - 5 mg/ml; for intravenous formulation suitable for the treatment of. systemic inflammation, shock, arthritis, allergies, asthma; for an oral formulation for the treatment of inflammatory bowel disease or general pain and inflammation a suitable dosage range would be 10-100 mg/kg. Bradykinin antagonists can also be administered intravaginally,
  • the present invention has a wide range of applicability to providing competitive inhibitors to the biological activities of bradykinin produced by the body in illness, injury and shock.
  • the advantages of the invention in substituting the L-Pro position 7 with amino acids of the D-configuration to convert bradykinin agonists to antagonists provide a wide variety of specific and competitive antagonists for reducing the known effects of bradykinin.
  • the additional advantages of the invention of modifying the L-Pro position 7 in conjunction with modifications at the other positions of the novel bradykinin antagonists provides a variety of useful compounds. It will further be appreciated the present invention is susceptible to these and other modifications within the parameters of the invention without departing from the scope of the following claims.

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Abstract

La substitution du L-Pro à la position 7 de la bradykinine d'hormone peptidique ou d'autres analogues substitués de bradykinine par un acide aminé aliphatique, cyclique ou aromatique, transforme les agonistes de bradykinine en un antagoniste de bradykinine. L'invention concerne en outre des modifications supplémentaires à d'autres positions à l'intérieur des nouveaux antagonistes de bradykine modifiés à la position 7, comprenant le remplacement de l'arginine dans les positions un et neuf, ainsi que les extensions des analogues relatifs à la délétion de séquences, et des terminaisons C et N, ce qui augmente la résistance enzymatique, la puissance et/ou la spécificité antagonistes des nouveaux antagonistes de bradykinine. Les analogues produits sont utiles dans le traitement de conditions et de maladies de mammifères et du corps humain chez qui un excédent de bradykinine ou de kinines apparentées est produit ou injecté comme par des morsures dans le corps.
EP19880908552 1987-09-02 1988-08-29 Bradykinin antagonist peptides Withdrawn EP0332688A4 (en)

Applications Claiming Priority (2)

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US9219287A 1987-09-02 1987-09-02
US92192 1987-09-02

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EP0332688A1 true EP0332688A1 (fr) 1989-09-20
EP0332688A4 EP0332688A4 (en) 1990-09-26

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EP (1) EP0332688A4 (fr)
JP (1) JPH02501224A (fr)
AU (1) AU2425388A (fr)
WO (1) WO1989001780A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334244A3 (fr) * 1988-03-25 1991-05-29 The Procter & Gamble Company Peptides antagonistes de Bradykinine
DE3926822A1 (de) * 1989-08-14 1991-02-21 Hoechst Ag Peptide mit bradykinin-antagonistischer wirkung
US5416191A (en) * 1991-04-01 1995-05-16 Cortech, Inc. Bradykinin antagonists
FR2739553B1 (fr) 1995-10-06 1998-01-02 Oreal Utilisation d'antagonistes de la bradykinine pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
JPWO2016129174A1 (ja) * 2015-02-09 2017-11-16 株式会社ファーマフーズ ヒアルロン酸産生促進剤

Family Cites Families (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

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JPH02501224A (ja) 1990-04-26
AU2425388A (en) 1989-03-31
WO1989001780A1 (fr) 1989-03-09
EP0332688A4 (en) 1990-09-26

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