1160995-19-6Relevant articles and documents
BICYCLIC INHIBITORS OF HISTONE DEACETYLASE
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, (2019/02/25)
Provided herein are compounds and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of conditions associated with inhibition of HDAC (e.g,. HDAC2).
Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90
Jiang, Fen,Wang, Hui-Jie,Jin, Yu-Hui,Zhang, Qiong,Wang, Zhi-Hui,Jia, Jian-Min,Liu, Fang,Wang, Lei,Bao, Qi-Chao,Li, Dong-Dong,You, Qi-Dong,Xu, Xiao-Li
, p. 10498 - 10519 (2016/12/16)
Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.