EFFICACIOUS, ORALLY BIOAVAILABLE THROMBIN INHIBITORS BASED ON 3-AMINOPYRIDINONE OR 3-AMINOPYRAZINONE ACETAMIDE PEPTIDOMIMETIC TEMPLATES

We have addressed the key deficiency of noncovalent pyridinone acetami de thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisost ere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), th e closest aminopyrazinone analogue of 1, has comparable selectivity an d slightly decreased efficacy but significantly improved pharmacokinet ics in rats, dogs, and monkeys to 1. We have developed an efficient an d versatile synthesis of 3, and this compound has been chosen for furt her preclinical and clinical development.