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Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors. 2007
Bin Ye, and
Damian O Arnaiz, and
Yuo-Ling Chou, and
Brian D Griedel, and
Rushad Karanjawala, and
Wheeseong Lee, and
Michael M Morrissey, and
Karna L Sacchi, and
Steven T Sakata, and
Kenneth J Shaw, and
Shung C Wu, and
Zuchun Zhao, and
Marc Adler, and
Sarah Cheeseman, and
William P Dole, and
Janice Ewing, and
Richard Fitch, and
Dao Lentz, and
Amy Liang, and
David Light, and
John Morser, and
Joseph Post, and
Galina Rumennik, and
Babu Subramanyam, and
Mark E Sullivan, and
Ron Vergona, and
Janette Walters, and
Yi-Xin Wang, and
Kathy A White, and
Marc Whitlow, and
Monica J Kochanny
Berlex Biosciences, Post Office Box 4099, Richmond, California 94804-0099, USA. rickbinye@yahoo.com
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.
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