强效异恶唑啉糖蛋白IIb/IIIa受体拮抗剂的发现。

Discovery of potent isoxazoline glycoprotein IIb/IIIa receptor antagonists.

作者信息

Wityak J, Sielecki T M, Pinto D J, Emmett G, Sze J Y, Liu J, Tobin A E, Wang S, Jiang B, Ma P, Mousa S A, Wexler R R, Olson R E

机构信息

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

出版信息

J Med Chem. 1997 Jan 3;40(1):50-60. doi: 10.1021/jm960626t.

DOI:10.1021/jm960626t

PMID:9016328

Abstract

Using the isoxazoline as a common structural feature, three series of glycoprotein IIb/IIIa receptor antagonists were evaluated, culminating in the discovery of XR299 (30). In an in vitro assay of platelet inhibition, XR299 had an IC50 of 0.24 microM and was a potent antiplatelet agent when dosed intravenously in a canine model. It was shown through X-ray studies of the cinchonidine salt 49 that the receptor required the 5(R)-stereochemistry for high potency. The ethyl ester prodrug of XR299, XR300 (29), was orally active in the dog.

摘要

以异恶唑啉作为共同结构特征，对三个系列的糖蛋白IIb/IIIa受体拮抗剂进行了评估，最终发现了XR299（30）。在血小板抑制的体外试验中，XR299的IC50为0.24微摩尔，在犬模型中静脉给药时是一种有效的抗血小板药物。通过对辛可尼定盐49的X射线研究表明，该受体需要5(R)-立体化学结构才能具有高效能。XR299的乙酯前药XR300（29）在犬体内具有口服活性。