title: 1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors.
abstract: A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain.
authors.affiliation: NeurAxon Inc., 2395 Speakman Drive, Suite #1001, Mississauga, ON, Canada L5K 1B3.
authors.forename: Shawn
authors.initials: S
authors.lastname: Maddaford
authors.forename: Paul
authors.initials: P
authors.lastname: Renton
authors.forename: Joanne
authors.initials: J
authors.lastname: Speed
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
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mladenova
authors.forename: Lisa
authors.initials: L
authors.lastname: Majuta
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D019001:Nitric Oxide Synthase