DISCOVERY OF AN ORALLY-ACTIVE SERIES OF ISOXAZOLINE GLYCOPROTEIN IIB IIIA ANTAGONISTS/

Using isoxazoline XR299 (1a) as a starting point for the design of hig hly potent, long-duration GPIIb/IIIa antagonists, the effect of placin g lipophilic substituents at positions alpha and beta to the carboxyla te moiety was evaluated. Of the compounds studied, it was found that t he n-butyl carbamate 24u(1,2) exhibited superior potency and, duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidi n-4-yl moiety with alternative basic groups, elimination of the isoxaz oline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.