The hit-to-lead optimization of 1,2,3,4,4a,9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists  

作　　者：Yan-Hui Zhu Meng Zhang Qun-Yi Li Qing Liu Jie Zhang Yun-Yun Yuan Fa-Jun Nan Ming-Wei Wang 

机构地区：[1]The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences [2]The CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences

出　　处：《Chinese Chemical Letters》2014年第5期693-698,共6页中国化学快报（英文版）

基　　金：supported in part by grants from the Ministry of Health of China (Nos. 2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001 and 2013ZX09507002);Shanghai Science and Technology Development Fund (No. 13DZ2290300);Thousand Talents Program in China

摘　　要：The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays.Four different regions of the scaffold were modified to assess the effects on hGRa antagonism and related potency.Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a,as well as an improved chemical stability,which make it a promising lead for the subsequent optimization.The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays.Four different regions of the scaffold were modified to assess the effects on hGRa antagonism and related potency.Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a,as well as an improved chemical stability,which make it a promising lead for the subsequent optimization.

关 键 词：Glucocorticoid receptor Antagonist 1 2 3 4 4a 9a-Hexahydroxanthene Structure–activity relationship Lead optimization 

分 类 号：TQ460.1[化学工程—制药化工]