Design and synthesis of substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor alpha/delta dual agonists.

A series of phenylpropanoic acids was prepared as candidate dual agonists of peroxisome proliferator-activated receptors (PPAR) alpha and delta. Structure-activity relationship studies indicated that the shape of the linker moiety and the nature of the substituent at the distal benzene ring play key roles in determining the potency and selectivity of PPAR subtype transactivation. Optically active alpha-ethylphenylpropanoic acid derivatives were identified as potent human PPAR alpha and delta dual agonists with potential for the treatment of metabolic syndrome.