Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors

被引：41

作者：

Ye, Bin ^{[1
]}

Arnaiz, Damian O. ^{[1
]}

Chou, Yuo-Ling ^{[1
]}

Griedel, Brian D. ^{[1
]}

Karanjawala, Rushad ^{[1
]}

Lee, Wheeseong ^{[1
]}

Morrissey, Michael M. ^{[1
]}

Sacchi, Karna L. ^{[1
]}

Sakata, Steven T. ^{[1
]}

Shaw, Kenneth J. ^{[1
]}

Wu, Shung C. ^{[1
]}

Zhao, Zuchun ^{[1
]}

Adler, Marc ^{[1
]}

Cheeseman, Sarah ^{[1
]}

Dole, William P. ^{[1
]}

Ewing, Janice ^{[1
]}

Fitch, Richard ^{[1
]}

Lentz, Dao ^{[1
]}

Liang, Amy ^{[1
]}

Light, David ^{[1
]}

Morser, John ^{[1
]}

Post, Joseph ^{[1
]}

Rumennik, Galina ^{[1
]}

Subramanyam, Babu ^{[1
]}

Sullivan, Mark E. ^{[1
]}

Vergona, Ron ^{[1
]}

Walters, Janette ^{[1
]}

Wang, Yi-Xin ^{[1
]}

White, Kathy A. ^{[1
]}

Whitlow, Marc ^{[1
]}

Kochanny, Monica J. ^{[1
]}

机构：

[1] Berlex Biosci, Richmond, CA 94804 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 13期

关键词：

D O I：

10.1021/jm070125f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.

引用

页码：2967 / 2980

页数：14

共 61 条

[1] Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa [J].