Abstract
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
MeSH terms
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Administration, Oral
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Aminopyridines / chemical synthesis*
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Aminopyridines / chemistry
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Aminopyridines / pharmacology
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Biological Availability
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Body Temperature / drug effects
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Calcium / metabolism
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Capsaicin
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Cell Line
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Humans
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Hypothermia / chemically induced
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Hypothermia / prevention & control
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Ion Channels / agonists
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Ion Channels / antagonists & inhibitors*
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Male
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Pain Measurement
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Rats
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Structure-Activity Relationship
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TRPV Cation Channels
Substances
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4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide
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Aminopyridines
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Analgesics
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Ion Channels
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Piperazines
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TRPV Cation Channels
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TRPV1 protein, human
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Trpv1 protein, rat
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Capsaicin
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Calcium