Substituted N-phenylisothioureas: potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity.
S-Ethyl N-phenylisothiourea (4) has been found to be a potent inhibitor of both the human constitutive and inducible isoforms of nitric oxide synthase. A series of substituted N-phenylisothiourea analogues was synthesized to investigate the structure-activity relationship of this class of inhibitor. Each analogue was evaluated for human isoform selectivity. One analogue, S-ethyl N-[4-(trifluoromethyl)phenyl]isothiourea (39), exhibited 115-fold and 29-fold selectivity for the neuronal isoform versus the inducible and endothelial derived constitutive isoforms, respectively. Studies have shown the substituted N-phenylisothiourea 39 binds competitively with L-arginine.
Shearer
B G
BG
Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. shearer-bg@glaxo.com
Lee
S
S
Oplinger
J A
JA
Frick
L W
LW
Garvey
E P
EP
Furfine
E S
ES
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D002956:Citrulline / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009474:Neurons / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007527:Isoenzymes; C106598:S-ethyl N-(4-(trifluoromethyl)phenyl)isothiourea; D002956:Citrulline; D001120:Arginine; D019001:Nitric Oxide Synthase; D013890:Thiourea