title: 1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors.
abstract: A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (-)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC(50)=0.02 μM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS=96-fold) and iNOS (iNOS/nNOS=850-fold) isoforms.
authors.affiliation: NeurAxon Inc., 2395 Speakman Drive, Suite #1001, Mississauga, ON, Canada L5K 1B3.
authors.forename: Paul
authors.initials: P
authors.lastname: Renton
authors.forename: Joanne
authors.initials: J
authors.lastname: Speed
authors.forename: Shawn
authors.initials: S
authors.lastname: Maddaford
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
authors.forename: Jailall
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: John
authors.initials: J
authors.lastname: Andrews
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D052248:Nitric Oxide Synthase Type I; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D052248:Nitric Oxide Synthase Type I