New 2-Aryloxy-3-phenyl-propanoic Acids As Potent Peroxisome Proliferator-Activated Receptors α/γ Dual Agonists Able to Upregulate the Mitochondrial Carnitine Shuttle System Gene Expression

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors.(1) The combination therapy with drugs acting on both PPARα and PPARγ isotypes may have synergistic and wider therapeutic effects improving both glucose and lipid metabolism and could be a new strategy in the treatment of metabolic syndrome. (1–4) In the recent past we have synthesized and reported the effects on human PPARα and PPARγ of chiral clofibric acid analogues, identifying LT175 as a lead compound.(2–4) With the aim to investigate the possibility to fine-tune the activity of this ligand, a new series of its analogs were synthesized in which different substituents were introduced on the aromatic rings of the diphenyl system (Figure 1). Noteworthy, we identified new ligands with higher potency on PPAR while maintaining basically unchanged the potency and the partial agonism on PPARγ. Considering the high degree of stereoselectivity displayed from these receptors towards LT175, most derivatives were synthesized only as the S-isomers. X-ray and calorimetric studies with PPARγ as well as docking experiments were performed for the most active compound S-15 and its corresponding isomer, providing a molecular explanation for their different activity. Finally, we investigated the effects of S-15 on the transcription of the mitochondrial carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes which are two molecular components of the carnitine shuttle system essential for the mitochondrial oxidation of fatty acids.