New 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors alpha/gamma dual agonists with improved potency and reduced adverse effects on skeletal muscle function

The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARα/γ dual agonist 1, allowed the identification of new ligands with improved potency on PPARα and unchanged activity on PPARγ. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARγ and docking experiments in PPARα provided a molecular explanation for their different behavior as full and partial agonists of PPARα and PPARγ, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.