A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects*
From the Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden, the ||Department of Structural Chemistry, **Department of Biology, Department of Medicinal Chemistry, Department of Assay Development and Screening, Biovitrum, SE-112 76 Stockholm, Sweden
The peroxisome proliferator-activated receptors (PPARs) areligand-activated transcription factors belonging to the NR1subfamily of nuclear receptors. The PPARs play key roles inthe control of glucose and lipid homeostasis, and the syntheticisoform-specific PPAR agonists are used clinically to improveinsulin sensitivity and to lower serum triglyceride levels.All of the previously reported PPAR agonists form the same characteristicinteractions with the receptor, which have been postulated tobe important for the induction of agonistic activity. Here wedescribe a new class of PPAR/ modulators, the 5-substituted2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography,the representative compounds BVT.13, BVT.762, and BVT.763, utilizea novel binding epitope and lack the agonist-characteristicinteractions. Despite this, some compounds within the 2-BABAfamily 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 designisoform-specific PPAR modulators with biological activity invivo.