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

被引：8

作者：

Chen, Liu ^{[1
,2
]}

Chen, Danqi ^{[2
]}

Tang, Le ^{[1
,2
]}

Ren, Jing ^{[2
]}

Chen, Jiaojiao ^{[3
]}

Zhen, Xuechu ^{[3
]}

Liu, Yu-Chih ^{[4
]}

Zhang, Chenhua ^{[4
]}

Luo, Haibin ^{[5
]}

Shen, Jingkang ^{[2
]}

Xiong, Bing ^{[2
]}

机构：

[1] Nanchang Univ, Sch Pharmaceut Sci, Nanchang 330006, Jiangxi, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

[3] Soochow Univ, Dept Pharmacol, Coll Pharmaceut Sci, Suzhou, Peoples R China

[4] Shanghai ChemPartner Co LTD, Pudong New Area, Bldg 5,998 Halei Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China

[5] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 13期

基金：

中国国家自然科学基金;

关键词：

Phosphodiesterase; PDE10A; Purine; Inhibitor; Anti-psychotic; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; ANIMAL-MODELS; SCHIZOPHRENIA; DISCOVERY; DISEASES; POTENT; IDENTIFICATION; TARGETS;

D O I：

10.1016/j.bmc.2017.04.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-alpyrazines 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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：3315 / 3329

页数：15

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