Design and optimization of purine derivatives as in vivo active PDE10A inhibitors. Issue 13 (1st July 2017)

• Record Type: Journal Article
• Authors: Chen, Liu; Chen, Danqi; Tang, Le; Ren, Jing; Chen, Jiaojiao; Zhen, Xuechu; Liu, Yu-Chih; Zhang, Chenhua; Luo, Haibin; Shen, Jingkang; Xiong, Bing
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 13(2017)
• Page Start: 3315
• Page End: 3329
• Publication Date: 2017-07-01
• Subjects: DIEA N, N-diisopropylethylamine -- DME dimethoxyethane -- DMF N, N-dimethylformamide -- EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -- HOBt 1-hydroxybenzotriazole -- rt room temperature -- TEA triethylamine -- THF tetrahydrofuran; Phosphodiesterase -- PDE10A -- Purine -- Inhibitor -- Anti-psychotic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.019
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.