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.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Cytochrome P-450 Enzyme Inhibitors
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Drug Discovery*
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ERG1 Potassium Channel
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics*
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Humans
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Ligation / adverse effects
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Male
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Migraine Disorders / drug therapy*
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Migraine Disorders / etiology
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Nitric Oxide Synthase Type I / antagonists & inhibitors*
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Rats
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Rats, Sprague-Dawley
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Spinal Nerves / surgery
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Structure-Activity Relationship
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Thiophenes / chemistry
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Thiophenes / pharmacokinetics*
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Thiophenes / pharmacology*
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Thiophenes / therapeutic use
Substances
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Cytochrome P-450 Enzyme Inhibitors
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ERG1 Potassium Channel
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Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Thiophenes
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Nitric Oxide Synthase Type I