Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes.
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 (IC(50) > 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.
Ijuin
Ryosuke
R
Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan.
Umezawa
Naoki
N
Nagai
Shin-ichi
S
Higuchi
Tsunehiko
T
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018411:Spodoptera
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D001120:Arginine; D019001:Nitric Oxide Synthase