Antiplatelet and antithrombotic agents: From viper venom proteins, to peptides and peptidomimetics, to small organic molecules

Abstract

The importance of developing thrombolytics for the treatment of myocardial infarction and other major coronary diseases cannot be disputed. The continued mortality and morbidity associated with cardiovascular disease justify the continued pursuit of newer and better therapies. As examples, Glycomed's Astenose was recently reported to cut restenosis 50-75% in baboons receiving injuries from balloon angioplasty, 175 Gensia's Protara (formerly arasine) is currently under review by the FDA prior to its approval for the prevention of myocardial infarction, and for use in coronary artery bypass surgery, 176 and the comparison of currently approved thrombolytic agents continues (i.e., streptokinase vs Activase (tPA), 3 and Activase (tPA) vs Eminase 177 ). Furthermore, in a report recently published in the Annals of Emergency Medicine , a government panel recently concluded that not enough heart attack patients are being treated with thrombolytic drugs, and further recommended that “clotbusting” agents ( Activase , tPA, Genentech; Eminase , SmithKline- Beecham; and streptokinase, Astra Pharmaceutical Products) should be kept in hospital emergency rooms, rather than hospital formularies, to save time. 178 Several synthetic peptides are in various stages of development as antithrombotics. Searle is pursuing the preclinical development of a pseudopeptide, 8-guanidino-octanoyl-Asp-Phe 179 ; Telios' cyclic peptide TP-9201 is currently being evaluated clinically 27 ; and Biogen is set to announce the results of TIMI-7 (thrombolysis in myocardial infarction) with its synthetic peptide thrombin inhibitor Hirulog. 20. , 180. COR Therapeutics will announce further results of Phase II studies with its synthetic peptide Integrelin, specifically on the issue raised in a recent study, in which it was found that the use of the drug produced an increase in the number of bleeding events over placebo. 180 The potency of the cyclic RGD peptides that have thus far been prepared have proved a boon to computational and synthetic chemists pursuing small molecule antagonists of GpllblIIa/Fg. Regardless of the actual conformation of R-G-D present in many of the natural proteins and cyclic peptides synthesized and studied, and the uncertainty surrounding the conformation of this critical epitope, the rigid constraint of RGD in these contexts provides a much clearer departure point for the design of molecules that can mimic RGD in this critical (though not necessarily native) conformation and good evidence of the power of "rational design." Other evidence of the expediency of rational design is beginning to surface in the literature, 181. , 182. , 183. perhaps proving that RGD is not unique in providing just such a design opportunity. As for the pursuit of small organic molecules as therapeutics, the best affirmation of the potential success that might be achieved is with the clinical development of argatroban by Houston Biotechnology Corporation. 21. , 184. Merck 185 and Roche 186 are currently pursuing preclinical and clinical studies of their small molecule antiplatelet GplIblIia antagonists. Certainly, the United States Pharmacopeia is replete with small organic molecules approved for use as drugs; small molecules can be used for oral administration, can be modified to improve absorption and/or clearance and minimize side effects, and are certainly more cost-effective to produce.