title: Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms.
abstract: A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 microM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
authors.affiliation: Department of Discovery Medicinal Chemistry, G. D. Searle Research and Development, Monsanto Company, St. Louis, Missouri 63198, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Webber
authors.forename: S
authors.initials: S
authors.lastname: Metz
authors.forename: W M
authors.initials: WM
authors.lastname: Moore
authors.forename: J R
authors.initials: JR
authors.lastname: Connor
authors.forename: M G
authors.initials: MG
authors.lastname: Currie
authors.forename: K F
authors.initials: KF
authors.lastname: Fok
authors.forename: T J
authors.initials: TJ
authors.lastname: Hagen
authors.forename: D W
authors.initials: DW
authors.lastname: Hansen
authors.forename: G M
authors.initials: GM
authors.lastname: Jerome
authors.forename: P T
authors.initials: PT
authors.lastname: Manning
authors.forename: B S
authors.initials: BS
authors.lastname: Pitzele
authors.forename: M V
authors.initials: MV
authors.lastname: Toth
authors.forename: M
authors.initials: M
authors.lastname: Trivedi
authors.forename: M E
authors.initials: ME
authors.lastname: Zupec
authors.forename: F S
authors.initials: FS
authors.lastname: Tjoeng
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000201:enzymology; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009474:Neurons / Q000201:enzymology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000097:blood; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007097:Imines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D010880:Piperidines; D011994:Recombinant Proteins; D019001:Nitric Oxide Synthase