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

被引：79

作者：

Xue, CB ^{[1
]}

Wityak, J ^{[1
]}

Sielecki, TM ^{[1
]}

Pinto, DJ ^{[1
]}

Batt, DG ^{[1
]}

Cain, GA ^{[1
]}

Sworin, M ^{[1
]}

Rockwell, AL ^{[1
]}

Roderick, JJ ^{[1
]}

Wang, SG ^{[1
]}

Orwat, MJ ^{[1
]}

Frietze, WE ^{[1
]}

Bostrom, LL ^{[1
]}

Liu, J ^{[1
]}

Higley, CA ^{[1
]}

Rankin, FW ^{[1
]}

Tobin, AE ^{[1
]}

Emmett, G ^{[1
]}

Lalka, GK ^{[1
]}

Sze, JY ^{[1
]}

DiMeo, SV ^{[1
]}

Mousa, SA ^{[1
]}

Thoolen, MJ ^{[1
]}

Racanelli, AL ^{[1
]}

Hausner, EA ^{[1
]}

Reilly, TM ^{[1
]}

DeGrado, WF ^{[1
]}

Wexler, RR ^{[1
]}

Olson, RE ^{[1
]}

机构：

[1] DUPONT MERCK PHARMACEUT CO,WILMINGTON,DE 19880

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 13期

关键词：

D O I：

10.1021/jm960799i

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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(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, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.

引用

页码：2064 / 2084

页数：21

共 56 条

[1] LOW-MOLECULAR-WEIGHT, NONPEPTIDE FIBRINOGEN RECEPTOR ANTAGONISTS [J].