Abstract
The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.
MeSH terms
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Administration, Oral
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Analgesics / chemical synthesis*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Animals
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Biological Availability
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Dogs
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Drug Stability
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Humans
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In Vitro Techniques
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Indazoles / chemical synthesis*
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Isoquinolines / chemical synthesis
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Isoquinolines / pharmacokinetics
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Isoquinolines / pharmacology
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Microsomes, Liver / metabolism
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Phenylurea Compounds / chemical synthesis*
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Phenylurea Compounds / pharmacokinetics
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Phenylurea Compounds / pharmacology
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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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Urea / analogs & derivatives*
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Urea / chemical synthesis
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Urea / pharmacokinetics
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Urea / pharmacology
Substances
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Analgesics
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Indazoles
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Isoquinolines
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N-(3-trichloromethyl-4-(8-azabicyclo(3.2.1)octan-8-yl)benzyl)-N'-(indazol-4-yl)urea
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Phenylurea Compounds
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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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Urea