A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to im...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-09, Vol.279 (39), p.41124-41130
Main Authors: Östberg, Tove, Svensson, Stefan, Selén, Göran, Uppenberg, Jonas, Thor, Markus, Sundbom, Maj, Sydow-Bäckman, Mona, Gustavsson, Anna-Lena, Jendeberg, Lena
Format: Article
Language:English
Subjects:
Animals
Benzoates - pharmacology
Benzophenones - chemistry
Crystallography, X-Ray
Dose-Response Relationship, Drug
Epitopes - chemistry
Genes, Reporter
Glucose - metabolism
Hypoglycemic Agents - pharmacology
Ligands
Lipid Metabolism
Male
Medicin och hälsovetenskap
Mice
Mice, Inbred C57BL
Models, Chemical
Models, Molecular
Protein Binding
Protein Isoforms
Receptors, Cytoplasmic and Nuclear - agonists
Rosiglitazone
Thiazolidinediones - pharmacology
Transcription Factors - agonists
Transcriptional Activation
Triglycerides - blood
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Summary:The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPARα/γ modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M401552200