Article ID Journal Published Year Pages File Type
1392793 European Journal of Medicinal Chemistry 2012 14 Pages PDF
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 (IC50 = 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 (Fpo = 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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A novel class of sixteen 1,5-disubstituted indoline derivatives were synthesized. ► These compounds were shown to be potent and selective inhibitors of human nNOS. ► These compounds mitigate cardiovascular liabilities (eNOS and hERG K+ activity). ► Therapeutic application was shown in two different pain (SNL and Migraine) models. ► Therapeutic application was further supported by safe side activity profile of 43.

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Physical Sciences and Engineering Chemistry Organic Chemistry
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