Sulindac derivatives that activate the peroxisome proliferator-activated receptor γ but lack cyclooxygenase inhibition

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 (PPAR gamma). Nonpolar and aromatic substitutions oil 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 my other in the series with,in EC50 Of 0-1 mu M for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPAR gamma was demonstrated by the displacement of I. 3 H]troglitazone, a PPAR gamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPAR gamma 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 PPAR gamma target genes. Taken together, these compounds represent potential leads in the development of novel PPAR gamma agonists.