Abstract
The discovery of peroxisome proliferator-activated receptor g (PPARg) antagonists (also termed ‘‘selective PPARg modulators, SPPARgM’’) 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 PPARg antagonist, is entirely different from that of other reported PPARg antagonists. A series of 35 novel analogues (1bel, 9aed, 13aet) 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 9aed) exhibited strong PPARg antagonistic activities (IC50 values of 5.2e25.8 mM) against 10 mM rosiglitazone in the promotion of the PPARgeLBDeCBP (ligand-binding domain and cAMP-response-element binding protein) interaction as investigated by yeast two-hybrid technology based assay. Molecular modeling studies for compounds 1aed, 1h, 9ced, and 13a were also presented.
 2008 Elsevier