Referenced in: none

Automatically associated channels: Kv11.1

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.

Authors: Subhash C Annedi, Shawn P Maddaford, Jailall Ramnauth, Paul Renton, Taras Rybak, Sarah Silverman, Suman Rakhit, Gabriela Mladenova, Peter Dove, John S Andrews, Dongqin Zhang, Frank Porreca

Journal, date & volume: Eur J Med Chem, 2012 Sep , 55, 94-107

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22840695

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.