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 PPAR±/³ dual agonist 1, allowed the identification of new ligands with improved potency on PPAR± and unchanged activity on PPAR³. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPAR³ and docking experiments in PPAR± provided a molecular explanation for their different behavior as full and partial agonists of PPAR± and PPAR³, 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.