Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 8; no. 24; pp. 3499 - 3504
• Main Authors: Xue, Chu-Biao, Roderick, John, Mousa, Shaker, Olson, Richard E., DeGrado, William F.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-12-1998; Elsevier
• Subjects: Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Dogs; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Isoxazole derivatives; Anticoagulant; Ex vivo; Structure activity relation; Fibrinogen; Piperidine derivatives; Antagonist; Chemical synthesis; Dog; Oxygen nitrogen heterocycle; Biological receptor; Human; Fissipedia; Carnivora; Glycoprotein IIbIIIa; Benzene derivatives; Oral administration; In vitro; Antiplatelet agent; In vivo; α-Aminoacid; Vertebrata; Amidine; Platelet; Mammalia; Animal; Affinity; Carboxamide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(98)00637-4

Despite the excellent in vitro potency of a series of benzamide glycoprotein IIb/IIIa antagonists, which have been reported previously, poor in vivo potency in the inhibition of platelet aggregation was observed when the most potent inhibitor
XU057 was dosed intravenously to dogs. In this communication, we report that replacement of the benzamide in
XU057 with an isoxazolecarboxamide resulted in significant improvement in in vivo potency. More importantly, the analogue
XU065 showed an excellent oral antiplatelet effect in dogs.
XU065 is a potent glycoprotein IIb/IIIa antagonist with an excellent oral antiplatelet effect in dogs.