Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists

…, DG Batt, GA Cain, M Sworin, AL Rockwell…

Index: 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. Journal of Medicinal Chemistry, 1997 , vol. 40, # 13 p. 2064 - 2084

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Citation Number: 66

Abstract

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 1, 2 exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, ...