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

作者信息

Xue C B, Wityak J, Sielecki T M, Pinto D J, Batt D G, Cain G A, Sworin M, Rockwell A L, Roderick J J, Wang S, Orwat M J, Frietze W E, Bostrom L L, Liu J, Higley C A, Rankin F W, Tobin A E, Emmett G, Lalka G K, Sze J Y, Di Meo S V, Mousa S A, Thoolen M J, Racanelli A L, Olson R E

机构信息

DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.

出版信息

J Med Chem. 1997 Jun 20;40(13):2064-84. 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 alpha and beta 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.