Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors
| Autor: | Wei Han, Patrick Y.S. Lam, Philip D. Stein, John E. Macor, Jing Zhang, Robert Zahler, Eddie C.-K. Liu, Karnail S. Atwal, Yan Shi, Ying Wang, Saleem Ahmad, Lawrence J. Kennedy, Stephen P. O'connor, S. M. Seiler, Jeffrey A. Robl, Zilun Hu, Doree F. Sitkoff |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Pyrrolidines Serine Proteinase Inhibitors Molecular model medicine.drug_mechanism_of_action medicine.drug_class Stereochemistry Clinical Biochemistry Factor Xa Inhibitor Pharmaceutical Science Carboxamide Biochemistry Pyrrolidine Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Molecular Biology chemistry.chemical_classification biology Chemistry Organic Chemistry Sulfonamide Piperazine Enzyme inhibitor biology.protein Molecular Medicine Bioisostere Factor Xa Inhibitors |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 17:5952-5958 |
| ISSN: | 0960-894X |
| Popis: | The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC50 of 5.5 nM and PT EC2x of 1.7 μM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets. |
| Databáze: | OpenAIRE |
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