Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa
| Autor: | Dao Lentz, Marc Whitlow, Kenneth J. Shaw, Karna Lyn Sacchi, Sakata Steven T, Janette Walters, Kathy White, Joseph Post, Bin Ye, Wheeseong Lee, Kochanny Monica, Elena Ho, Amy Liang, Ron Vergona, Janice Ewing, Morrissey Michael M, Karanjawala Rushad E, Gary Phillips, Zuchun Zhao, Brian D. Griedel, Babu Subramanyam, Marc Adler |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Models Molecular Magnetic Resonance Spectroscopy Serine Proteinase Inhibitors Molecular model medicine.drug_mechanism_of_action Stereochemistry Clinical Biochemistry Factor Xa Inhibitor Substituent Pharmaceutical Science Thiophenes Crystallography X-Ray Biochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Discovery Thiophene medicine Animals Humans Molecular Biology chemistry.chemical_classification biology Organic Chemistry Amides Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine Amine gas treating Factor Xa Inhibitors |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:2127-2146 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2006.12.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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