iNOSダイマー形成阻害薬の治療薬としての可能性
スポンサーリンク
概要
- 論文の詳細を見る
Nitric oxide (NO) plays an important role in various physiological processes. NO is synthesized by a family of NO synthases (NOS). Among the three isoforms of NOS, inducible NOS (iNOS) is closely related to inflammatory and autoimmune diseases. The suppression of excess NO production in participating cells may be helpful in improving disease status. NO inhibitors acting via the new mechanism of dimerization of iNOS are reviewed. The oxygenase domains of two NOS monomers interact to form a dimer, and the NOS isoforms are only active as homodimers. 3-(2,4-difluorophenyl)-6-{2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy}-2-phenylpyridine (PPA250), N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide (Compound 2) and other imidazole derivatives inhibit this step and cause the inhibition of NO production. Crystallographic studies have shown that Compound 2 blocks dimerization through coordinating the heme in the iNOS monomer. PPA250 suppressed the development of arthritis after clinical symptoms had appeared in animal models. PPA250 and Compound 2 also decreased the serum concentration of NO in mice treated with lipopolysaccharide. These results indicate that inhibitors of iNOS homodimerization could be useful therapeutic agents for rheumatoid arthritis, septic shock and other diseases in which NO is involved. In addition, these inhibitors may present new research tools for exploring iNOS dimerization processes.
- 2003-03-10