| Literature DB >> 19541481 |
Yan Shi1, 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.
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, K(i)=6.5nM, EC(2xPT)=32muM) 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.Entities:
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Year: 2009 PMID： 19541481 DOI： 10.1016/j.bmcl.2009.06.014
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823