1. Cross Reference To Related Applications
The invention pertains to new and useful bradykinin antagonist peptides and is related to the subject matter of U.S. application Ser. Nos. 092,148, 092,179, and 092,192 all filed on Sept. 2, 1987.
2. Field Of The Invention
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 the substitution of L-Pro at position 7 to convert bradykinin agonists into antagonists together with other modifications and substitutions at other positions including C and N-terminal extensions and modifications, amino acid deletions and the substitution of arginine in the one and nine positions of the novel bradykinin antagonists.
3. Description Of The Prior Art
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 (Hirsrh et al., J. Surg. Res. 17:147, 1974), anaphylaxis, (Collier and James, J. Physiol. 160:15P, 1966), arthritis (Jasani et al., Am. Rheum. Dis. 28:497, 1969; Hamberg et al., Agents Actions 8:50, 1978; Sharma et al., Arch. Int. Pharmacodyn 262:279, 1983), rhinitis (Proud et al., J. Clin. Invest. 72:1678, 1983; Naclerio et al., Clin. Res. 33:613A, 1985), asthma (Christiansen et al., J. Clin. Invest. 79:188-197, 1987), inflammatory bowel disease (Zeitlin and Smith, Gut 14:133-138, 1973), and certain other conditions including acute pancreatitis, post-gastrectomy dumping syndrome, carcinoid syndrome, migraine, and angioneurotic edema (Leme, Handb. Exp. Pharmacol. 50/I:464-522, 1978). 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.
The production of 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 signaling the pain of myocardial ischeamia.
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.
The search for understanding of the mechanism of action of 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.
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 (Gecse 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. 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) (Gecse, Adv. Exptl. Biol. Med. 70: 5, 1976), the dipeptide Phe-Gly (Gecse 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. Bicl. 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.
Preparations of damaged vascular tissue have been reported to respond to bradykinin analogs which lack the C-terminal Arg residue, but not to bradykinin itself, and analogs of these des-Arg.sup.9 -bradykinins have been developed as antagonists of this non-physiological activity of bradykinin. These antagonists have no significant bradykinin-like agonist effects, nor any antagonist effect on any of the physiologically significant kinin-responding systems (Regoli and Barabe, Pharmacol. Revs. 32:1,1980).
Several 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).
Other changes in the bradykinin molecule have been additions of amino acids at the N-terminal end which affect the rate of enzymatic degradation of bradykinin in vivo.
The half life of 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. Resistance of bradykinin agonists to pulmonary kininase destruction in vivo is promoted by addition of single (i.e., 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).