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

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