Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.
Basic Information
ID: ALA1144944
Journal: J Med Chem
Title: Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.
Authors: Choi-Sledeski YM, Kearney R, Poli G, Pauls H, Gardner C, Gong Y, Becker M, Davis R, Spada A, Liang G, Chu V, Brown K, Collussi D, Leadley R, Rebello S, Moxey P, Morgan S, Bentley R, Kasiewski C, Maignan S, Guilloteau JP, Mikol V.
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.
CiteXplore: 12593648
DOI: 10.1021/jm020384z
Patent ID: ┄