N2-Aroylanthranilamide Inhibitors of Human Factor Xa
| Autor: | Linebarger Jh, Michael Robert Wiley, Leonard C. Weir, Trelia J. Craft, Goodson T, Donetta S. Gifford-Moore, Kyle Ja, Jason Scott Sawyer, Valentine J. Klimkowski, David K. Herron, Anne Louise Tebbe, Smith Gf, Douglas W. Beight, Ying Kwong Yee, Jennifer M. Tinsley, Richard D. Towner |
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| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular medicine.drug_mechanism_of_action Molecular model Stereochemistry Factor Xa Inhibitor Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Amide Drug Discovery medicine Humans Structure–activity relationship Enzyme Inhibitors Binding site chemistry.chemical_classification Sulfonamides Binding Sites biology Anticoagulants Sulfonamide chemistry Enzyme inhibitor Benzamides Factor Xa biology.protein Molecular Medicine Factor Xa Inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 43:873-882 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Reversal of the A-ring amide link in 1,2-dibenzamidobenzene 1 (fXa K(ass) = 0.81 x 10(6) L/mol) led to a series of human factor Xa (hfXa) inhibitors based on N(2)-aroylanthranilamide 4. Expansion of the SAR around 4 showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of hfXa. Bulky groups such as 4-isopropyl, 4-tert-butyl, and 4-dimethylamino were favored in the B-ring to interact with the S4 site of hfXa. The central (C) ring containing a 5-methanesulfonamido group yielded greater activity than carbamoyl groups. Combining the beneficial features from the B- and C-ring SAR, compound 55 represents the most potent hfXa inhibitor in the N(2)-aroylanthranilamide 4 series with hfXa K(ass) = 58 x 10(6) L/mol (K(i) = 11.5 nM). |
| Databáze: | OpenAIRE |
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