Characterization of Telmisartan‐Derived PPARγ Agonists: Importance of Moiety Shift from Position 6 to 5 on Potency, Efficacy and Cofactor Recruitment

Abstract

Selective modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure-lowering properties, the AT1-receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure-activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzofuran (agonists 6-5 and 6-6) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC50 values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3-L1 cells and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC-1 and PGC-1α, and release of corepressor NCoR1 determined by time-resolved fluorescence resonance energy transfer (TR-FRET) was detected depending on residues in position 5 or 6.

Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists

“…Partials agonists are defined as weak activators of PPARγ that elicit the same activation pattern as full agonists, but with a lower maximal activity. The antihypertensive agent Telmisartan is an angiotensin II receptor antagonist, but it has also been reported to function as a weak PPARγ agonist. , Scientists at GlaxoSmithKline optimized the telmisartan scaffold to afford GSK 7b, as a potent PPARγ partial agonist (Figure A) . A group at Amgen developed AMG-131 as a potent and highly selective PPARγ partial agonist that advanced into Phase 2 clinical trials .…”

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

“…Through structure–activity relationship analysis of 72 , Matthias Goebel found that 1-(biphenyl-4-ylmethyl)-1 H -benzimidazole scaffold is an essential moiety (Figure ). The alkyl chains at C-2, such as ethyl or propyl, are appropriate for dual activities, while the methyl group at C-4 contributes to partial activity. , Substitution at C-5 is not conducive to ATI antagonism and PPARγ activation . The hydrophobic substitution at position 6 will help to enhance the activity of PPARγ without affecting the antagonism of ATI. , Yann Lamotte demonstrated that the replacement of the 1-methylbenzimidazole group in position 6 of 72 by an easily accessible carboxamide revealed a potent PPARγ partial agonist GSK7b. , …”

“…164,165 Substitution at C-5 is not conducive to ATI antagonism and PPARγ activation. 166 The hydrophobic substitution at position 6 will help to enhance the activity of PPARγ without affecting the antagonism of ATI. 164,167 Yann Lamotte demonstrated that the replacement of the 1methylbenzimidazole group in position 6 of 72 by an easily accessible carboxamide revealed a potent PPARγ partial agonist GSK7b.…”