Tryptophan-containing dipeptide derivatives as potent PPARγ antagonists: Design, synthesis, biological evaluation, and molecular modeling

Abstract: The discovery of peroxisome proliferator-activated receptor γ (PPARγ) antagonists (also termed “selective PPARγ modulators, SPPARγM”) is now of a great interest in the treatment of diabetes and obesity. The structure of compound 1a (G3335, Fig. 1), a novel class of PPARγ antagonist, is entirely different from that of other reported PPARγ antagonists. A series of 35 novel analogues (1b–l, 9a–d, 13a–t) were designed, synthesized and evaluated against the agonistic effects exerted by rosiglitazone. These results indicated that most functional groups of 1a were conserved, and six new compounds (1b, 1c, and 9a–d) exhibited strong PPARγ antagonistic activities (IC50 values of 5.2–25.8μM) against 10μM rosiglitazone in the promotion of the PPARγ–LBD–CBP (ligand-binding domain and cAMP-response-element binding protein) interaction as investigated by yeast two-hybrid technology based assay. Molecular modeling studies for compounds 1a–d, 1h, 9c–d, and 13a were also presented. [Copyright &y& Elsevier]