2. Academic Validation
  3. Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors

Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors

  • Bioorg Med Chem Lett. 2009 Aug 1;19(15):4034-41. doi: 10.1016/j.bmcl.2009.06.014.
Yan Shi 1,  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 Jr,  Eddie C-K Liu,  Karen S Hartl,  Steve M Seiler,  Thomas E Steinbacher,  William A Schumacher,  Karnail S Atwal,  Philip D Stein
Affiliations

Affiliation

  • 1 Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. [email protected]
PMID: 19541481 DOI: 10.1016/j.bmcl.2009.06.014
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.

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