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

Abstract

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.

Structural basis for telmisartan-mediated partial activation of PPAR gamma

“…The overall fold was almost identical to previously determined apo and complex structures, [28][29][30] and comprised of 12 helices (H1-H12) and a small b-sheet region of four strands (Figure 1a). We superposed Ca atoms from the structure of PPARg with telmisartan onto those from the structure with rosiglitazone (PDB ID: 2PRG), 29 2-BABA (PDB ID: 1WM0) 30 and the apo structure (PDB ID: 1PRG), 29 and calculated root mean square deviations. The root mean square deviations were 0.64 Å for rosiglitazone, 0.69 Å for 2-BABA and 0.93 Å for the apo structure.…”

“…Although we obtained plate-like crystals that belonged to space group C2 from the solution containing PPARg and telmisartan and found lattices similar to those found when PPARg LBD formed complexes with other agonists, [28][29][30] we did not observe telmisartan in the determined structure.…”

“…Previous structural analysis of PPARg with partial agonists has also revealed that the binding modes of coactivator-derived peptides are virtually identical to that seen for PPARg with rosiglitazone. 30,40 Although some partial agonists including telmisartan are known to exhibit selectivity for coactivators, the reason behind this selectivity cannot be determined by observing complex structures. It is possible that selectivity is generated through subtle differences in dynamics.…”

S 26948

“…It is well known that most PPAR␥ ligands are able to normalize glycemia and insulinemia in spite of increasing body weight (22,24). This has first been observed with TZDs in animal studies (31,32,51) and then confirmed in mildly obese humans treated with such compounds (33,34).…”

“…1F). However, the finding that it has no effect on adipogenesis-in addition to the significant effect in reducing atherosclerosis-showed functional differences with rosiglitazone and other PPAR␥ agonists (21)(22)(23)(24)(25)(26)(27). This establishes S 26948 as a new specific PPAR␥ modulator that is able to drive normal adipocyte differentiation-in contrast to rosiglitazone, which exacerbates this process.…”