Abstract
4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Benzamides / chemical synthesis*
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Benzamides / pharmacokinetics
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Benzamides / pharmacology
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Binding Sites
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Carnitine O-Palmitoyltransferase / biosynthesis
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Carnitine O-Palmitoyltransferase / genetics
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Cell Line, Tumor
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Cysteine / metabolism
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Drug Screening Assays, Antitumor
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Genes, Reporter
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Humans
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Ligands
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Male
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Mass Spectrometry
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Mice
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Mice, Inbred C57BL
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / enzymology
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PPAR delta / agonists
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PPAR delta / antagonists & inhibitors*
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PPAR delta / genetics
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / pharmacokinetics
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Sulfones / pharmacology
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Tissue Distribution
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Transcription, Genetic / drug effects
Substances
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4-chloro-N-(2-((5-trifluoromethyl-2-pyridyl)sulfonyl)ethyl)benzamide
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Antineoplastic Agents
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Benzamides
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Ligands
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PPAR delta
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Sulfones
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Carnitine O-Palmitoyltransferase
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Protein Serine-Threonine Kinases
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Cysteine