title: Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors.
abstract: Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain.
authors.affiliation: NeurAxon Inc., Mississauga, Ontario, Canada. jramnauth@neuraxon.com
authors.forename: Jailall
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Joanne
authors.initials: J
authors.lastname: Speed
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Maddaford
authors.forename: Peter
authors.initials: P
authors.lastname: Dove
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
authors.forename: Paul
authors.initials: P
authors.lastname: Renton
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: John
authors.initials: J
authors.lastname: Andrews
authors.forename: Sarah
authors.initials: S
authors.lastname: Silverman
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mladenova
authors.forename: Salvatore
authors.initials: S
authors.lastname: Zinghini
authors.forename: Sheela
authors.initials: S
authors.lastname: Nair
authors.forename: Concettina
authors.initials: C
authors.lastname: Catalano
authors.forename: David K H
authors.initials: DK
authors.lastname: Lee
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D009437:Neuralgia / Q000188:drug therapy; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; C542964:1,2,3,4-tetrahydroquinoline; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I