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Bioorg Med Chem. 2007 Mar 1;15(5):2127-46. Epub 2006 Dec 13.

Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa.

Author information

1
Berlex Biosciences, PO Box 4099, Richmond, CA 94804-0099, USA. Monica_Kochanny@berlex.com

Abstract

A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.

PMID:
17227710
DOI:
10.1016/j.bmc.2006.12.019
[Indexed for MEDLINE]

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