Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1).

We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR α/γ dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR α/γ dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR α/γ dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model.