title: 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate.
abstract: Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 (  J. Med. Chem.     2011  ,   54  ,   5562 - 5575  ). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC(50) = 4.7 μM). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC(50) > 30 μM). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate.
authors.affiliation: NeurAxon Inc., 2395 Speakman Drive, Suite 1001, Mississauga, Ontario, L5K 1B3, Canada. jramnauth@neuraxon.com
authors.forename: Jailall
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Paul
authors.initials: P
authors.lastname: Renton
authors.forename: Peter
authors.initials: P
authors.lastname: Dove
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Annedi
authors.forename: Joanne
authors.initials: J
authors.lastname: Speed
authors.forename: Sarah
authors.initials: S
authors.lastname: Silverman
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mladenova
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Maddaford
authors.forename: Salvatore
authors.initials: S
authors.lastname: Zinghini
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: John
authors.initials: J
authors.lastname: Andrews
authors.forename: David K H
authors.initials: DK
authors.lastname: Lee
authors.forename: Dongqin
authors.initials: D
authors.lastname: Zhang
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D057166:High-Throughput Screening Assays; D006801:Humans; D009437:Neuralgia / Q000188:drug therapy; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C573845:N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide; D011804:Quinolines; D054852:Small Molecule Libraries; D013876:Thiophenes; D052248:Nitric Oxide Synthase Type I