Abstract
A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.
MeSH terms
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Aminopyridines / chemistry*
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Aminopyridines / pharmacokinetics
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Aminopyridines / pharmacology
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Analgesics / chemistry*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Animals
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Body Temperature / drug effects
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CHO Cells
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Calcium / metabolism
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Capsaicin / pharmacology
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Cricetulus
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Freund's Adjuvant
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Ganglia, Spinal / cytology
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Humans
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Hydrogen-Ion Concentration
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Male
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Pain / drug therapy*
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Pain / etiology
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Rats, Sprague-Dawley
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Sensory Receptor Cells / drug effects
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Sensory Receptor Cells / physiology
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Stereoisomerism
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Structure-Activity Relationship
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TRPV Cation Channels / antagonists & inhibitors*
Substances
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4-(3-chloro-5-(1,2-dihydroxyethyl)-2-pyridyl)-N-(5-(trifluoromethyl)-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxamide
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Aminopyridines
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Analgesics
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TRPV Cation Channels
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TRPV1 protein, human
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Freund's Adjuvant
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Capsaicin
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Calcium