Referenced in: none

Automatically associated channels: Kv11.1

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 p

Authors: Jailall Ramnauth, Paul Renton, Peter Dove, Subhash C Annedi, Joanne Speed, Sarah Silverman, Gabriela Mladenova, Shawn P Maddaford, Salvatore Zinghini, Suman Rakhit, John Andrews, David K H Lee, Dongqin Zhang, Frank Porreca

Journal, date & volume: J. Med. Chem., 2012 Mar 22 , 55, 2882-93

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22335555

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.