Design and optimization of purine derivatives as in vivo active PDE10A inhibitors

Publication date: 1 July 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
Author(s): Liu Chen, Danqi Chen, Le Tang, Jing Ren, Jiaojiao Chen, Xuechu Zhen, Yu-Chih Liu, Chenhua Zhang, Haibin Luo, Jingkang Shen, Bing Xiong
Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2-a]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin.

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