Neutral macrocyclic factor VIIa inhibitors
| Autor: | Jiang Wen, Anzhi Wei, Ruth R. Wexler, Jeffrey M. Bozarth, Dietmar A. Seiffert, Joseph M. Luettgen, Delucca Indawati, Nicholas R. Wurtz, Pancras C. Wong, T.W. Harper, Brandon Parkhurst, Xiaojun Zhang, Daniel L. Cheney, E. Scott Priestley, Peter W. Glunz, Yiming Wu, Alan R. Rendina |
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| Rok vydání: | 2016 |
| Předmět: |
Macrocyclic Compounds
Serine Proteinase Inhibitors Membrane permeability Stereochemistry Clinical Biochemistry Binding pocket Pharmaceutical Science Factor VIIa Pharmacology 01 natural sciences Biochemistry Structure-Activity Relationship Drug Discovery Antithrombotic Potency Humans Molecular Biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Limiting 0104 chemical sciences 010404 medicinal & biomolecular chemistry Orally active Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 27(12) |
| ISSN: | 1464-3405 |
| Popis: | Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability. |
| Databáze: | OpenAIRE |
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