Abstract
We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Acetamides / chemistry*
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Acetamides / metabolism
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Acetamides / therapeutic use
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Aminopyridines / chemistry*
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Aminopyridines / metabolism
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Aminopyridines / therapeutic use
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Animals
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Capsaicin / toxicity
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Cystitis / chemically induced
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Cystitis / drug therapy
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Drug Design*
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Drug Evaluation, Preclinical
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Humans
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Protein Binding
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Rats
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Structure-Activity Relationship
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TRPV Cation Channels / antagonists & inhibitors*
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TRPV Cation Channels / metabolism
Substances
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Acetamides
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Aminopyridines
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TRPV Cation Channels
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TRPV1 protein, human
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acetamide
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Capsaicin