Design, Synthesis, and Activity of 2-Imidazol-1-ylpyrimidine Derived Inducible Nitric Oxide Synthase Dimerization Inhibitors
| Autor: | Damian Arnaiz, Gary Phillips, Shawn David Erickson, Marc Whitlow, Margaret Kenrick, James J. Devlin, Gonghua Pan, Cecile Santos, William J. Guilford, Robert G. Wei, Marc Adler, Kurt W. Saionz, Bin Ye, Ron Vergona, John Parkinson, Zuchun Spring Zhao, David D. Davey, Michael Ohlmeyer, Babu Subramanyam, Vidyadhar M. Paradkar, Mark A. Polokoff, Keith A. Eagen, Michael M. Morrissey |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Models Molecular Gene isoform Nitric Oxide Synthase Type II Crystallography X-Ray Chemical synthesis Cell Line Nitric oxide chemistry.chemical_compound Oxidoreductase Chlorocebus aethiops Drug Discovery Animals Benzodioxoles Binding site chemistry.chemical_classification biology Chemistry Anti-Inflammatory Agents Non-Steroidal Imidazoles Biological activity Arthritis Experimental Rats Nitric oxide synthase Pyrimidines Enzyme Biochemistry Rats Inbred Lew biology.protein Molecular Medicine Dimerization |
| Zdroj: | Journal of Medicinal Chemistry. 50:1146-1157 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm061319i |
| Popis: | By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS. |
| Databáze: | OpenAIRE |
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