title: Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS).
abstract: A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K(+) channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels).
authors.affiliation: NeurAxon Inc., 2395 Speakman Drive, Suite # 1001, Mississauga, ON, Canada L5K 1B3. sannedi@neuraxon.com
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
authors.forename: Jailall
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Michele
authors.initials: M
authors.lastname: Cossette
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Maddaford
authors.forename: Peter
authors.initials: P
authors.lastname: Dove
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: John S
authors.initials: JS
authors.lastname: Andrews
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013127:Spinal Nerves / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D001552:Benzazepines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III