Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand

  • J Med Chem. 2003 Feb 27;46(5):681-4. doi: 10.1021/jm020384z.
Yong Mi Choi-Sledeski  1 ,  Robert Kearney ,  Gregory Poli ,  Henry Pauls ,  Charles Gardner ,  Yong Gong ,  Michael Becker ,  Roderick Davis ,  Alfred Spada ,  Guyan Liang ,  Valeria Chu ,  Karen Brown ,  Dennis Collussi ,  Robert Leadley Jr ,  Sam Rebello ,  Phillip Moxey ,  Suzanne Morgan ,  Ross Bentley ,  Charles Kasiewski ,  Sebastien Maignan ,  Jean-Pierre Guilloteau ,  Vincent Mikol
Affiliations
  • 1. Department of Medicinal Chemistry and Department of Biology, Aventis Pharmaceuticals, Route 202-206, Bridgewater, New Jersey 08807-0800, USA. [email protected]
PMID: 12593648 DOI: 10.1021/jm020384z
Abstract

The discovery and SAR of ketopiperazino methylazaindole Factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.

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