title: Tryptophan-containing dipeptide derivatives as potent PPARgamma antagonists: design, synthesis, biological evaluation, and molecular modeling.
abstract: The discovery of peroxisome proliferator-activated receptor gamma (PPARgamma) antagonists (also termed "selective PPARgamma modulators, SPPARgammaM") 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 PPARgamma antagonist, is entirely different from that of other reported PPARgamma 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 PPARgamma antagonistic activities (IC(50) values of 5.2-25.8 microM) against 10 microM rosiglitazone in the promotion of the PPARgamma-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.
authors.affiliation: Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Deng
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D003198:Computer Simulation; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000032:analysis / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D047495:PPAR gamma; D014364:Tryptophan