The discovery of peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonists (also termed "selective PPAR gamma modulators, SPPAR gamma M") is now of a great interest in the treatment of diabetes and obesity. The structure of compound la (G3335, Fig. 1), a novel class of PPAR gamma antagonist, is entirely different from that of other reported PPAR gamma antagonists. A series of 35 novel analogues (1b-1, 9a-d, 13a-t) were designed, synthesized and evaluated against the agonistic effects exerted by rosiglitazone. These results indicated that most functional groups of la were conserved, and six new compounds (1b, 1c, and 9a-d) exhibited strong PPAR gamma antagonistic activities (IC50 values of 5.2-25.8 mu M) against 10 mu M rosiglitazone in the promotion of the PPAR gamma-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. (C) 2008 Elsevier Masson SAS. All rights reserved.
