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 PPAR␣/␥ 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.

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Receptor binding activityReceptor binding activity X 0280 Synthesis and Pharmacological Evaluation of a New Class of Peroxisome Proliferator-Activated Receptor Modulators. -Three different series of 5-substituted 2-benzoylaminobenzoic acids such as (I), (II), and (III) are synthesized as PPARα/ γ modulators by using the Mitsunobu reaction and Suzuki coupling. The 5-substituted BVT.142 analogues (I), (IIa), and (IIb) are dual PPARα/γ agonists showing significantly more activity than the original hit, while compounds (IIc) and (IId) are potent and highly selective PPARγ agonists. Diaryl ethers (III) show the highest binding affinities and are highly selective as well. The new class activates the PPARγ receptor through interaction with a novel binding site. -(THOR*, M.; et al.; Bioorg. Med. Chem. Lett. 12 (2002) 24, 3565-3567; Dep. Med. Chem., Biovitrum AB, S-751 37 Uppsala, Swed.; Eng.) -H. Hoennerscheid 12-220

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