Characterization of new PPARgamma agonists: analysis of telmisartan's structural components

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 (PPARgamma). Based on these findings and an excellent side-effect profile, telmisartan may serve as a lead structure for the development of new PPARgamma ligands. Therefore, we analyzed the structural components of telmisartan to identify those necessary for PPARgamma 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-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV. The data obtained in this structure-activity relationship (SAR) study provide the basis for the development of new PPARgamma 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.