Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors
| Autor: | Yuo-Ling Chou, John Morser, Marc Adler, Wheeseong Lee, Joseph Post, David R. Light, Kochanny Monica, Karna Lyn Sacchi, Dao Lentz, Arnaiz Damian O, Marc Whitlow, Bin Ye, Amy Liang, Ron Vergona, Richard W. Fitch, Mark E. Sullivan, Sarah Cheeseman, Janice Ewing, Zuchun Zhao, Babu Subramanyam, Kathy White, Kenneth J. Shaw, Karanjawala Rushad E, Janette Walters, Brian D. Griedel, Yi-Xin Wang, William P. Dole, Michael M. Morrissey, Steven T. Sakata, Galina Rumennik, Shung C. Wu |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Models Molecular medicine.drug_mechanism_of_action medicine.drug_class Factor Xa Inhibitor Aminopyridines Thiophenes Pharmacology In Vitro Techniques Crystallography X-Ray Structure-Activity Relationship Dogs Oral administration In vivo Drug Discovery medicine Potency Animals Humans ortho-Aminobenzoates Rats Wistar Serine protease Venous Thrombosis biology Chemistry Drug discovery Anticoagulant Anticoagulants Amides Rats Biochemistry Enzyme inhibitor biology.protein Prothrombin Time Molecular Medicine Factor Xa Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 50(13) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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