Discovery of New Thienopyrimidine Derivatives as Potent and Orally Efficacious Phosphoinositide 3-Kinase Inhibitors

Publication date: Available online 23 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Songwen Lin, Chunyang Wang, Ming Ji, Deyu Wu, Yuanhao Lv, Li Sheng, Fangbin Han, Yi Dong, Kehui Zhang, Yakun Yang, Yan Li, Xiaoguang Chen, Heng Xu
A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.

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