Rhodanine derivatives as novel peroxisome proliferator-activated receptor γ agonists

作     者：Qing LIU,Yue-yun ZHANG,Hui-li LU,Qun-yi LI,Cai-hong ZHOU,Ming-wei WANG~2The National Center,for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China 

作者机构：The National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China 

出 版 物：《Acta Pharmacologica Sinica》 (中国药理学报(英文版))

年 卷 期：2007年第28卷第12期

页      面：2033-2039页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：Project supported in part by grants from the Shanghai Municipality Science and Technology Development Fund(№ 05dZ22914 and 06DZ22907) the Ministry of Science and Technology(№ 2004CB518902) 

主　　题：rhodanine derivatives peroxisome proliferator-activated receptor structure-activity relationship adipogenesis 

摘      要：Aim:To characterize the in vitro bioactivities of rhodanine derivatives as novelperoxisome proliferator-activated receptor (PPAR)γ modulators,based on a hit(SH00012671) identified during high-throughput screening (HTS) of a diversesynthetic compound library,and to preliminarily elucidate the structure-activityrelationship of this class of PPARγ ***:Full-length PPARγ andretinoid X receptor α(RXRα),biotinylated PPAR response element (PPRE),[~3H]BRL49653 (rosiglitazone),and streptavidin-coated FlashPlate or microbeadswere used to measure the receptor-binding properties of various compounds basedon the scintillation proximity assay (SPA) technology.A recombinant PPRE vec-tor was transiently cotransfected with PPARγ and RXRα plasmids into the Africangreen monkey kidney (CV-1) cells,and the effects of BRL49653 and test com-pounds on transcription mediated by PPARγ were determined by examining lu-ciferase (reporter) responses.3T3-L1 cells were employed to determine whetherthe compounds facilitated adipogenesis upon PPARγ ***:Of the16 000 samples screened with the SPA method,only 1 compound (SH00012671)displayed a similar binding affinity (Ki=186.7 nmol/L) to PPARγ as BRL49653,butit was inactive in the cell-based assays.A series of rhodanine derivatives weresynthesized based on the core structure of SH00012671 and 8 of them showedagonist activities in both cotransfection and pre-adipocyte differentiation *** reduce intrinsic cytotoxicities,the sulphur on the rhodanine was changed *** alteration led to a decrease in receptor-binding affinities while modi-fied analogues generally maintained agonist efficacies in the cell-based *** the analogues studied,compound 31 exhibited about 70% the efficacy exertedby BRL49653 in both cotransfection and pre-adipocyte differentiation ***:Through minor chemical modifications on the core structure of theinitial HTS hit,SH00012671 was transformed to possess both molecular (PPARγ