The plasma kinins--kallidin and bradykinin--are polypeptides produced in-vivo which possess an extrordinarily high degree of pharmacological activity. They are the most potent vasodilator autacoids of mammals. In very low concentration they increase capillary permeability; produce edema; evoke pain and reflexes by acting on nerve endings; contract or relax various smooth muscles; and elicit various other responses in the body. In all these respects, bradykinin and kallidin behave very similarly.
These vasoactive kinins are cleaved from polypeptide or proteinl precursors in the plasma a.sub.2 -globulin fraction known as kininogens. This cleavage is the result of a select group of serine proteases, collectively referred to as kininogenases--of which the best known are the kallikreins; a group of enzymes of high substrate specificity that are present in plasma, in body tissues such as kidney and in various exocrine glands such as the pancreas. The specificity of each kallikrein is very high: plasma kallikreins release the nonapeptide kinin, bradykinin, directly from a kininogen of high (approximately 100,000 daltons) molecular weight (hereinafter "HMW kininogen"). Glandular and other tissue kallikreins release the decapeptide kinin, kallidin, from a kininogen of low (approximately 50,000 daltons) molecular weight (hereinafter "LMW kininogen"). Other proteolytic enzymes such as trypsin can release kinins non-specifically from various kininogens. Trypsin, however, does not circulate in the body and tissue kallikreins are believed to be the natural source of circulating kallekreins.
The kinins, bradykinin and kallidin, once produced, have a very short existence; their half-life in plasma is only about 15 seconds. The principle reason for their destruction in-vivo is the dipeptidyl carboxypeptidase known in this context as kininase II and in most other circumstances as angiotensin converting-enzyme (hereinafter "ACE"). This angiotensin converting enzyme is now well recognized as being responsible for the conversion of angiotensin I to the active angiotensin II which is directly involved in hypertension and debilitating hypertensive conditions. With the rise and use of effective anti-hypertensive drugs such as enalapril and captopril which act directly to inhibit ACE and markedly decrease production of angiotensin II, the consequential side-effect has been to unintensionally increase the quantities of vasoactive kinins circulating in the body. Thus, by acting affirmatively to control hypertension by inhibiting the enzymatic activity of ACE, this has resulted directly in unwanted and undesirable quantities of active kinins which react adversely in-vivo.
In addition to the foregoing problem, the capacity of human urinary kallikrein (a glandular kallikrein) to produce active kinin peptides has been of major concern in the intrarenal regulation of blood pressure [Levinsky, N. G., Circ. Res. 44: 441-451 (1979)]. One prevalent view is that kinin production in the kidneys is a major influence over if not a cause of, clinically observable hypotension and ortho-static hypotension. Equally important, recent reports have described urinary kallikrein and kallikrein-like proteases to function in the processing of prohormones or proenzymes such as prorenin, proinsulin, atriopeptigen, tissue plasminogen activator, nerve growth factors, and epidermal growth factors. For both clinical and research purposes, therefore, compounds demonstrating specific activity as kallikrein inhibitors continue to be sought.
Recently, a variety of kinin analogues having some kinin-like activity were evaluated. The kinins may act either directly on the vascular smooth muscle or indirectly by causing the release of endoplasmic derived relaxing factors (EDRF) from the vascular intima [Stewart, J. M. in Handbook Of Experimental Pharmacology, Volume 25 (supplement), New York, Springer-Verlag, 1979, pages 227-285]. Subsequently, a series of protease inhibitors which were not specific for glandular kallikreins and often possess undesirable biological activity themselves (such as the ability to induce hypotension) were evaluated. These included: aprotinin [Fritz et al., Fed. Proc. 38: 2753-2759 (1979); Seto et al., Hypertension 5: 893-899 (1983)]; benzamidine [Vogel, R., "Kallikrein Inhibitors", in Handbook Of Experimental Pharmacology, Volume 25 (supplement), New York, 1979, pages 163-225)]; aromatic diamidines [Geratz, J. D., J. Med. Chem. 16: 970-973 (1973); Geratz, et al., Arch. Int. Pharm. Ther. 194: 359-370 (1971)]; and peptides of arginine chloromethyl ketones [Kettner et al., Arch. Biochem. Biophys. 202: 420-430 (1980)]. Even more recently, there has been some investigation of substrate analogues based on the amino acid sequence of bovine kininogen and the capacity of such analogues to inhibit human urinary kallikrein [Okunishi et al., Hypertension 7 (suppl. I): I-72-I-75 (1985)]. Despite this accumulated body of knowledge, there remains the continuing problem of developing highly specific kallikrein inhibitors which are not rapidly cleaved and degraded; and which are demonstratably functional in-vivo to inhibit the activity of glandular kallikreins.