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Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics

文献类型：期刊论文

作者Xiamuxi, Hainimu2,4; Wang, Zhen3; Li, Jianfeng3; Wang, Yu3; Wu, Chunhui1; Yang, Feipu3; Jiang, Xiangrui3; Liu, Yongjian1; Zhao, Qingjie3; Chen, Weiming4
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2017-09-01
卷号25期号:17页码:4904-4916
关键词Dopamine Serotonin Multireceptor Atypical antipsychotic 5-HT1A
ISSN号0968-0896
DOI10.1016/j.bmc.2017.07.040
文献子类Article
英文摘要In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D-2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for alpha(1A), 5-HT2C, H-1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development. (C) 2017 Elsevier Ltd. All rights reserved.
WOS关键词SEROTONIN 5-HT1A RECEPTORS ; WEIGHT-GAIN ; SCHIZOPHRENIA ; DRUGS ; PHARMACOTHERAPY ; TARGETS ; UPDATE ; RATS
资助项目Special Foundation of Chinese Academy of Sciences for strategic pilot technology[XDA12040208] ; R&D Program of Shanghai Municipal Science and Technology Commission[14431905500]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000407831300033
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/272514]  
专题药物化学研究室
通讯作者Aisa, Haji Akber; He, Yang
作者单位1.Topharman Shanghai Co Ltd, 1088 Chuansha Rd, Shanghai 201209, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Peoples R China;
推荐引用方式
GB/T 7714		 Xiamuxi, Hainimu,Wang, Zhen,Li, Jianfeng,et al. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2017,25(17):4904-4916.
APA Xiamuxi, Hainimu.,Wang, Zhen.,Li, Jianfeng.,Wang, Yu.,Wu, Chunhui.,...&Shen, Jingshan.(2017).Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics.BIOORGANIC & MEDICINAL CHEMISTRY,25(17),4904-4916.
MLA Xiamuxi, Hainimu,et al."Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics".BIOORGANIC & MEDICINAL CHEMISTRY 25.17(2017):4904-4916.

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来源：上海药物研究所

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