Abstract
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / pharmacokinetics
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Animals
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Antihypertensive Agents / chemical synthesis
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Antihypertensive Agents / chemistry*
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Antihypertensive Agents / pharmacokinetics
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Cyclohexanols / chemical synthesis
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Cyclohexanols / chemistry*
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Cyclohexanols / pharmacokinetics
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Hyperthermia, Induced
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Isoxazoles / chemical synthesis
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Isoxazoles / chemistry*
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Isoxazoles / pharmacokinetics
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Rats
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Rats, Wistar
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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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Amides
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Antihypertensive Agents
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Cyclohexanols
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Isoxazoles
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TRPV Cation Channels
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Trpv1 protein, rat