Identification and characterization of a selective peroxisome proliferator-activated receptor beta/delta (NR1C2) antagonist.
The identification of small molecule ligands for the peroxisome proliferator-activated receptors (PPARs) has been instrumental in elucidating their biological roles. In particular, agonists have been the focus of much of the research in the field with relatively few antagonists being described and all of those being selective for PPARalpha or PPARgamma. The comparison of these agonist and antagonist ligands in cellular and animal systems has often led to surprising results and new insights into the biology of the PPARs. The PPARbeta/delta receptor is emerging as an important regulator of energy metabolism, inflammation, and cell growth and differentiation; however, only agonist ligands have been described for this receptor thus far. Here we describe the first report of a PPARbeta/delta small molecule antagonist ligand. This antagonist ligand will be a useful tool for elucidating the biological roles of PPARbeta/delta.
Shearer
Barry G
BG
Research and Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Steger
David J
DJ
Way
James M
JM
Stanley
Thomas B
TB
Lobe
David C
DC
Grillot
Didier A
DA
Iannone
Marie A
MA
Lazar
Mitchell A
MA
Willson
Timothy M
TM
Billin
Andrew N
AN
D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047494:PPAR delta / Q000037:antagonists & inhibitors*; D048068:PPAR-beta / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
D005227:Fatty Acids; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C529769:GSK0660; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds