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Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2007 Mar 22; Vol. 50 (6), pp. 1146-57. Date of Electronic Publication: 2007 Feb 23. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Animals
Anti-Inflammatory Agents, Non-Steroidal chemistry
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Arthritis, Experimental therapy
Benzodioxoles chemistry
Benzodioxoles pharmacology
Cell Line
Chlorocebus aethiops
Crystallography, X-Ray
Dimerization
Imidazoles chemistry
Imidazoles pharmacology
Male
Models, Molecular
Pyrimidines chemistry
Pyrimidines pharmacology
Rats
Rats, Inbred Lew
Anti-Inflammatory Agents, Non-Steroidal chemical synthesis
Benzodioxoles chemical synthesis
Imidazoles chemical synthesis
Nitric Oxide Synthase Type II metabolism
Pyrimidines chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 50
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17315988
- Full Text :
- https://doi.org/10.1021/jm061319i