American Chemical Society
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Thiophene-Anthranilamides as Highly Potent and Orally Available Factor Xa Inhibitors

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journal contribution
posted on 2007-06-28, 00:00 authored by Bin Ye, Damian O. Arnaiz, Yuo-Ling Chou, Brian D. Griedel, Rushad Karanjawala, Wheeseong Lee, Michael M. Morrissey, Karna L. Sacchi, Steven T. Sakata, Kenneth J. Shaw, Shung C. Wu, Zuchun Zhao, Marc Adler, Sarah Cheeseman, William P. Dole, Janice Ewing, Richard Fitch, Dao Lentz, Amy Liang, David Light, John Morser, Joseph Post, Galina Rumennik, Babu Subramanyam, Mark E. Sullivan, Ron Vergona, Janette Walters, Yi-Xin Wang, Kathy A. White, Marc Whitlow, Monica J. Kochanny
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.