Characterization of New PPARγ Agonists: Analysis of Telmisartan’s Structural Components

Telmisartan was originally designed as an AT1 antagonist but was later also characterized as a selective PPARγ modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPARγ activation activity, elucidating the individual SAR of each different component (shown). magnified image In addition to a proven efficacy in lowering blood pressure, the AT1 receptor blocker telmisartan has recently been shown to exert pleiotropic effects as a partial agonist of the nuclear peroxisome proliferator‐activated receptor gamma (PPARγ). Based on these findings and an excellent side‐effect profile, telmisartan may serve as a lead structure for the development of new PPARγ ligands. Therefore, we analyzed the structural components of telmisartan to identify those necessary for PPARγ activation. Synthesized compounds were tested in a differentiation assay using 3T3‐L1 preadipocytes and a luciferase assay with COS‐7 cells transiently transfected with pGal4‐hPPARγDEF, pGal5‐TK‐pGL3 and pRL‐CMV. The data obtained in this structure–activity relationship (SAR) study provide the basis for the development of new PPARγ ligands, which could lead to active compounds with a distinct, beneficial pharmacological profile compared with the existing full agonists. The basic 1‐(biphenyl‐4‐ylmethyl)‐1H‐benzimidazole scaffold of telmisartan was identified as an essential moiety with either a carboxylic acid or tetrazole group at the C‐2 position of the biphenyl. For maximum potency and activity, the alkyl chain in position 2 requires a minimum length of at least two C atoms (ethyl group), while the methyl group at position 4 of the benzimidazole core seems to contribute to partial activity. An additional benzimidazole at position 6 appears to be a further determinant of potency. Similar conclusions can be drawn for the methyl group in position 1.