A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 microM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARgamma was demonstrated by the displacement of [(3)H]troglitazone, a PPARgamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes. Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.