Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa
| Autor: | Danny J. Garland, Wei Huang, Michael S. South, Matthew W. Mahoney, Zaheer Abbas, David B. Reitz, John I. Trujillo, William L. Neumann, Carrie L. Kusturin, Horng-Chih Huang, Scott A. Long |
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| Rok vydání: | 2007 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Factor VIIa Biochemistry Chemical synthesis Thromboplastin Amidine Structure-Activity Relationship Tissue factor chemistry.chemical_compound Drug Discovery Molecular Biology Pyrans chemistry.chemical_classification Serine protease Molecular Structure biology Chemistry Organic Chemistry Anticoagulants Bioavailability Dissociation constant Enzyme Enzyme inhibitor Drug Design biology.protein Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 17:4568-4574 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2007.05.090 |
| Popis: | Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [ J. Med. Chem. 2003 , 46 , 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (p K a ∼ 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF–VIIa inhibitor. |
| Databáze: | OpenAIRE |
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