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High-affinity Peroxisome Proliferator-Activated Receptor β/δ-specific Ligands With Pure Antagonistic or Inverse Agonistic Properties

High-affinity Peroxisome Proliferator-Activated Receptor β/δ-specific Ligands With Pure Antagonistic or Inverse Agonistic Properties

Simone Naruhn, Philipp M Toth, Till Adhikary, Kerstin Kaddatz, Veronika Pape, Stefanie Dörr, Gerhard Klebe, Sabine Müller-Brüsselbach, Wibke E Diederich, Rolf Müller

Mol Pharmacol. 2011 Nov;80(5):828-38.

PMID: 21862691

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	CAS Number	Price
AP1356497910	ST247	1356497-91-0	Price
AP1356497921	PT-S58	1356497-92-1	Price
IAR4246434	PPARβ/δ Antagonist, PT-S58		Price

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