Discovery of an Orally Active Series of Isoxazoline Glycoprotein IIb/IIIa Antagonists

• Published in: Journal of medicinal chemistry 1997-06, Vol.40 (13), p.2064-2084
• Main Authors: Xue, Chu-Biao, Wityak, John, Sielecki, Thais M, Pinto, Donald J, Batt, Douglas G, Cain, Gary A, Sworin, Michael, Rockwell, Arlene L, Roderick, John J, Wang, Shuaige, Orwat, Michael J, Frietze, William E, Bostrom, Lori L, Liu, Jie, Higley, C. Anne, Rankin, F. Wayne, Tobin, A. Ewa, Emmett, George, Lalka, George K, Sze, Jean Y, Di Meo, Susan V, Mousa, Shaker A, Thoolen, Martin J, Racanelli, Adrienne L, Hausner, Elizabeth A, Reilly, Thomas M, DeGrado, William F, Wexler, Ruth R, Olson, Richard E
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Blood Platelets - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Dogs; Drug Design; Female; Isoxazoles - administration & dosage; Isoxazoles - chemistry; Isoxazoles - pharmacology; Macaca mulatta; Male; Medical sciences; Models, Chemical; Papio; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960799i

Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions α and β to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u , exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.