Biological Evaluation of New Fluorinated Analogues With PPARα and PPARγ Agonist Activity

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 MS39 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 fluorine atom or trifluoromethyl group were introduced on the aromatic rings in place of chlorine or as additional substituents. Fluoro or trifluoromethyl substituents generally have a profound effect on the physical and/or biological properties of the target molecule. Their introduction, in fact, beyond improving metabolic stability by blocking metabolically labile sites, can modulate physicochemical properties, such as lipophilicity or acidity, change molecular conformation, and increase binding affinity by exploiting specific interactions of F with the target protein.[5] The biological activity on PPAR isoforms of all new synthesized derivatives was evaluated by the transactivation assay, a powerful and widely used assay whose good correlation with in vivo activity is generally accepted. [2–4]