Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action

Modification of the cc-carbamate substituent of isoxazoline GPIIb/IIIa (alp ha(IIb)beta(3)) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were fo und to be potent inhibitors of in vitro platelet aggregation. Aryl- and het eroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S) -diaminopropionate stereochemistry, were found to impart a pronounced durat ion of antiplatelet effect in dogs, potentially due to high affinity for un activated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selectiv e GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high-affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a onc e-daily antiplatelet agent.