Novel Pirinixic Acids as PPARα Preferential Dual PPARα/γ Agonists

Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that alpha-alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR alpha and PPAR gamma. Taking alpha-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPAR gamma activity but further increased PPAR alpha activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR alpha ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantio-selective preparative HPLC respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.