A novel series of orally active antiplatelet agents

Abstract A novel series of orally active fibrinogen receptor antagonists has been discovered through structural modification of our lead intravenous (iv) antiplatelet agent, 5-(4-amidinophenyl)pentanoyl-Asp-Phe 1 (SC-52012). The Asp-Phe amide bond was removed through truncation to a 3-substituted β-amino acid aspartate mimetic which resulted in a tripeptide mimetic inhibitor of lower molecular weight (from 482 to the 330–390 g mol −1 ). The zwitterionic nature of the inhibitor was masked through the preparation of an ethyl ester prodrug. A lead compound from this series, 5-(4-amidinophenyl)pentanoyl-3-(3-pyridyl)propanoic acid 19a , was found to be a potent inhibitor of canine platelet aggregation in vitro (collagen, platelet rich plasma, PRP, IC 50 = 270 nM). In further canine studies, oral administration of different ester pro-drugs of 19a at 10 mg kg −1 resulted in the following oral systemic activities: pivaloyloxymethyl ester derivative 19p (5.1 ± 1.5% OSA), cyclohexyl ester derivative 19c (9.2 ± 1.9% OSA), and ethyl ester derivative 19e (9.9 ± 2.3% OSA).