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

Liu Chen; Danqi Chen; Le Tang; Jing Ren; Jiaojiao Chen; Xuechu Zhen; Yu-Chih Liu; Chenhua Zhang; Haibin Luo; Jingkang Shen; Bing Xiong

doi:10.1016/j.bmc.2017.04.019

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

Bioorg Med Chem. 2017 Jul 1;25(13):3315-3329. doi: 10.1016/j.bmc.2017.04.019. Epub 2017 Apr 13.

Authors

Liu Chen¹, Danqi Chen², Le Tang¹, Jing Ren², Jiaojiao Chen³, Xuechu Zhen³, Yu-Chih Liu⁴, Chenhua Zhang⁴, Haibin Luo⁵, Jingkang Shen⁶, Bing Xiong⁷

Affiliations

¹ School of PharmaceuticalSciences, Nanchang University, Nanchang 330006, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
² Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
³ Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, China.
⁴ Shanghai ChemPartner Co., LTD, Building 5, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
⁵ School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China.
⁶ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: jkshen@simm.ac.cn.
⁷ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: bxiong@simm.ac.cn.

PMID: 28462841
DOI: 10.1016/j.bmc.2017.04.019

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.

Keywords: Anti-psychotic; Inhibitor; PDE10A; Phosphodiesterase; Purine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dose-Response Relationship, Drug
Drug Design*
Humans
Locomotion / drug effects
Male
Mice
Microsomes / chemistry
Microsomes / metabolism
Molecular Structure
Phosphoric Diester Hydrolases / metabolism*
Prepulse Inhibition / drug effects
Purines / chemical synthesis
Purines / chemistry
Purines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Purines
PDE10A protein, human
Phosphoric Diester Hydrolases
purine