Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes

被引:17
作者
Ijuin, R [1 ]
Umezawa, N [1 ]
Nagai, S [1 ]
Higuchi, T [1 ]
机构
[1] Nagoya City Univ, Grad Sch Pharmaceut Sci, Mizuho Ku, Nagoya, Aichi 4678603, Japan
关键词
nitric oxide; nitric oxide synthase; inhibitor; arginine; docking study;
D O I
10.1016/j.bmcl.2005.03.078
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). In developing candidate clinical drugs, it is very important not to inhibit endothelial NOS, because it plays an important role in maintaining normal blood pressure and flow. Here, we describe the design, synthesis and human NOS-inhibitory activities of S-methyl-L-isothiocitrulline-based 3-substituted arginine analogs. The 3R*-methyl compound 4, which has an S-methyl isothiourea moiety, inhibited nNOS and iNOS, but not eNOS (IC50 > 1 mM). However, the 3R*-methyl compound 7, bearing a 5-iminoethyl moiety, did not inhibit any of the NOS isozymes, although L-N-iminoethylornithine (L-NIO) potently inhibited all three. A computational docking study was carried out to investigate the mechanism of the isozyme selectivity. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2881 / 2885
页数:5
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