2. Academic Validation
  3. Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577

Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577

  • Bioorg Med Chem Lett. 2009 Dec 15;19(24):6882-9. doi: 10.1016/j.bmcl.2009.10.084.
Yan Shi 1,  Chi Li,  Stephen P O'Connor,  Jing Zhang,  Mengxiao Shi,  Sharon N Bisaha,  Ying Wang,  Doree Sitkoff,  Andrew T Pudzianowski,  Christine Huang,  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. yan.shi@bms.com
PMID: 19896847 DOI: 10.1016/j.bmcl.2009.10.084
Abstract

We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.

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