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J Med Chem. 2003 Feb 27;46(5):681-4.

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

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Department of Medicinal Chemistry and Department of Biology, Aventis Pharmaceuticals, Route 202-206, Bridgewater, New Jersey 08807-0800, USA.


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.

[Indexed for MEDLINE]

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