Design, synthesis, and evaluation of new type of L-amino acids containing pyridine moiety as nitric oxide synthase inhibitor.
New amino acids 7-12 were designed and synthesized as candidate inhibitors of human nitric oxide synthase (NOS). The 2-aminopyridine-containing l-amino acids 8 had potent inhibitory activity toward all of the human NOS isozymes. However, the regioisomers 9 and 10, and 2-methylpyridine-containing compound 11 had much lower inhibitory activity. Human NOS isozymes were also inhibited by 7, which lacks an amino group on the pyridine moiety. A computational docking study was carried out to investigate the mechanism of the inhibitory effect.
Ijuin
Ryosuke
R
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
Umezawa
Naoki
N
Higuchi
Tsunehiko
T
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013329:Structure-Activity Relationship
D000596:Amino Acids; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011725:Pyridines; D011994:Recombinant Proteins; D019001:Nitric Oxide Synthase