title: High-affinity peroxisome proliferator-activated receptor β/δ-specific ligands with pure antagonistic or inverse agonistic properties.
abstract: Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a ligand-regulated nuclear receptor with essential functions in metabolism and inflammation. We have synthesized a new derivative [methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247) structurally related to the published PPARβ/δ inhibitory ligand methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (GSK0660). ST247 has a higher affinity to PPARβ/δ than GSK0660, and at equimolar concentrations, it more efficiently 1) induces the interaction with corepressors both in vitro and in vivo, 2) inhibits the agonist-induced transcriptional activity of PPARβ/δ, and 3) down-regulates basal level expression of the peroxisome proliferator responsive element-driven PPARβ/δ target gene ANGPTL4. Methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (PT-S58), another high-affinity derivative from our series, also efficiently inhibits agonist-induced transcriptional activation, but in contrast to ST247, it does not enhance the interaction of PPARβ/δ with corepressors. PT-S58 rather prevents corepressor recruitment triggered by the inverse agonist ST247. These findings classify ST247 as an inverse agonist, whereas PT-S58 is the first pure PPARβ/δ antagonist described to date. It is noteworthy that ST247 and PT-S58 are also effective on PPRE-independent functions of PPARβ/δ: in monocytic cells, both ligands modulate expression of the activation marker CCL2 in the opposite direction as an established PPARβ/δ agonist. The possibility to differentially modulate specific functions of PPARβ/δ makes these novel compounds invaluable tools to advance our understanding of PPARβ/δ biology.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Naruhn
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Toth
authors.forename: Till
authors.initials: T
authors.lastname: Adhikary
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kaddatz
authors.forename: Veronika
authors.initials: V
authors.lastname: Pape
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dörr
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008024:Ligands; D051379:Mice; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000378:metabolism*; D013876:Thiophenes / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D013449:Sulfonamides; D013876:Thiophenes; C585354:methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate