Synthesis and evaluation of trans 3,4-cyclopropyl -arginine analogues as isoform selective inhibitors of nitric oxide synthase
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- 作者：Fishlock ; Dan ; Perdicakis ; Basil ; Montgomery ; Heather J. ; Guillemette ; J. Guy ; Jervis ; Eric ; et. al.
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2003
- 出版时间：March, 2003
- 年：2003
- 卷：11
- 期：6
- 页码：869-873
- 全文大小：150 K
文摘
Four optically pure conformationally restricted l-arginine analogues syn- 1 and anti- 2 trans-3,4-cyclopropyl l-arginine, and syn- 3 and anti-trans-3,4-cyclopropyl N-(1-iminoethyl) l-ornithine 4 were synthesized. These compounds were tested as potential inhibitors against the three isoforms of nitric oxide synthase (NOS). Compound 1 was determined to be a poor substrate of NOS, while compound 2 was determined to be a poor mixed type inhibitor and did not exhibit any isoform selectivity. Syn- 3 and anti-trans-3,4-cyclopropyl N-(1-iminoethyl) l-ornithine 4 were found to be competitive inhibitors of NOS. These compounds were time dependent inhibitors of inducible NOS (iNOS), but not of neuronal NOS (nNOS) or endothelial NOS (eNOS). Compound 3 was 10- to 100-fold more potent an inhibitor than 4, exhibited a 5-fold increase in nNOS/iNOS and eNOS/iNOS selectivity over 4, and displayed tight binding characteristics against iNOS. These results indicate that the relative configuration of the cyclopropyl ring in the l-arginine analogues significantly affects their inhibitory potential and NOS isoform selectivity.