Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors |
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Authors: | Yan Shi Jing Zhang Mengxiao Shi Stephen P. O’Connor Sharon N. Bisaha Chi Li Doree Sitkoff Andrew T. Pudzianowski Saeho Chong Herbert E. Klei Kevin Kish Joseph Yanchunas Eddie C.-K. Liu Karen S. Hartl Steve M. Seiler Thomas E. Steinbacher William A. Schumacher Karnail S. Atwal Philip D. Stein |
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Affiliation: | Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA |
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Abstract: | The N,N′-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, Ki = 6.5 nM, EC2xPT = 32 μM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand–protein interactions are discussed. |
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