title: Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine.
abstract: We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K(+) channel inhibition (IC(50) = 4.7 μM) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure-activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F(po) = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain.
authors: NeurAxon Inc., 2395 Speakman Drive, Suite #1001, Mississauga, ON, Canada L5K 1B3. sannedi@vibrantpharma.com
authors: Subhash C
authors: SC
authors: Annedi
authors: Shawn P
authors: SP
authors: Maddaford
authors: Jailall
authors: J
authors: Ramnauth
authors: Paul
authors: P
authors: Renton
authors: Taras
authors: T
authors: Rybak
authors: Sarah
authors: S
authors: Silverman
authors: Suman
authors: S
authors: Rakhit
authors: Gabriela
authors: G
authors: Mladenova
authors: Peter
authors: P
authors: Dove
authors: John S
authors: JS
authors: Andrews
authors: Dongqin
authors: D
authors: Zhang
authors: Frank
authors: F
authors: Porreca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008026:Ligation / Q000009:adverse effects; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy* / Q000209:etiology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000601:surgery; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D013876:Thiophenes; D052248:Nitric Oxide Synthase Type I