title: Novel potent and selective inhibitors of inducible nitric oxide synthase.
abstract: We have identified two novel potent and selective inhibitors of inducible nitric oxide synthase, S-ethylisothiourea and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. Ki values of 14.7 nM for S-ethylisothiourea and 4.2 nM for 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine were obtained with partially purified preparations of inducible nitric oxide synthase. These compounds demonstrate about 1000-fold greater potency than prototypical inhibitors, and the inhibitions are 10-40-fold more selective for murine inducible nitric oxide synthase, compared with the rat neuronal and bovine endothelial isoforms of nitric oxide synthase. These compounds also potently inhibit the nitric oxide synthase activity in intact J774 mouse macrophages. The inhibition is competitive with the substrate L-arginine and reversible in both enzymatic and intact cell assays. These potent and selective inhibitors of inducible nitric oxide synthase may have potential therapeutic applications in the treatment of inflammatory and autoimmune diseases.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nakane
authors.forename: V
authors.initials: V
authors.lastname: Klinghofer
authors.forename: J E
authors.initials: JE
authors.lastname: Kuk
authors.forename: J L
authors.initials: JL
authors.lastname: Donnelly
authors.forename: G P
authors.initials: GP
authors.lastname: Budzik
authors.forename: J S
authors.initials: JS
authors.lastname: Pollock
authors.forename: F
authors.initials: F
authors.lastname: Basha
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D051381:Rats; D013843:Thiazines / Q000494:pharmacology*; D019323:omega-N-Methylarginine
chemical_list: C093124:2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine; D007527:Isoenzymes; D013843:Thiazines; D019335:Nitroarginine; D007550:Isothiuronium; C007687:etiron; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases