title: Substituted N-phenylisothioureas: potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity.
abstract: 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.
authors.affiliation: Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. shearer-bg@glaxo.com
authors.forename: B G
authors.initials: BG
authors.lastname: Shearer
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: J A
authors.initials: JA
authors.lastname: Oplinger
authors.forename: L W
authors.initials: LW
authors.lastname: Frick
authors.forename: E P
authors.initials: EP
authors.lastname: Garvey
authors.forename: E S
authors.initials: ES
authors.lastname: Furfine
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C106598:S-ethyl N-(4-(trifluoromethyl)phenyl)isothiourea; D002956:Citrulline; D001120:Arginine; D019001:Nitric Oxide Synthase; D013890:Thiourea