Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist.
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.
Department of Metabolic Chemistry, Metabolic Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA. barry.g.shearer@gsk.com
Barry G
BG
Shearer
Robert W
RW
Wiethe
Adam
A
Ashe
Andrew N
AN
Billin
James M
JM
Way
Thomas B
TB
Stanley
Craig D
CD
Wagner
Robert X
RX
Xu
Lisa M
LM
Leesnitzer
Raymond V
RV
Merrihew
Todd W
TW
Shearer
Michael R
MR
Jeune
John C
JC
Ulrich
Timothy M
TM
Willson
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D014158:Transcription, Genetic / Q000187:drug effects
C547957:4-chloro-N-(2-((5-trifluoromethyl-2-pyridyl)sulfonyl)ethyl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D008024:Ligands; D047494:PPAR delta; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013450:Sulfones; D002334:Carnitine O-Palmitoyltransferase; D017346:Protein Serine-Threonine Kinases; D003545:Cysteine