Design, synthesis, and evaluation of a novel series of α-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) α/δ dual agonists for the treatment of metabolic syndrome

A series of α-alkyl-substituted phenylpropanoic acids was prepared as dual agonists of peroxisome proliferator-activated receptors alpha and delta (PPARα/δ). Structure-activity relationship studies indicated that the shape of the linking group and the shape of the substituent at the distal benzene ring play key roles in determining the potency and the selectivity of PPAR subtype transactivation. Structure-activity relationships among the amide series (10) and the reversed amide series (13) are similar, but not identical, especially in the case of the compounds bearing a bulky hydrophobic substituent at the distal benzene ring, indicating that the hydrophobic tail part of the molecules in these two series binds at somewhat different positions in the large binding pocket of PPAR. α-Alkyl-substituted phenylpropanoic acids of (S)-configuration were identified as potent human PPARα/δ dual agonists. Representative compounds exhibited marked nuclear receptor selectivity for PPARα and PPARδ. Subtype-selective PPAR activation was also examined by analysis of the mRNA expression of PPAR-regulated genes.