Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors

doi:10.1039/c5ra04714e

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第二研究室

	Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors
	Liu, Yang 1; Guo, Lin 2,3; Duan, Hongliang 1; Zhang, Liming 1; Jiang, Neng 4; Zhen, Xuechu 2,3; Shen, Jianhua1
刊名	RSC ADVANCES
	2015
卷号	5 期号:51 页码:40964-40977
ISSN号	2046-2069
DOI	10.1039/c5ra04714e
文献子类	Article
英文摘要	Regulation of glycine transporter 1 (GlyT1) activity is a currently investigated strategy in drug discovery for schizophrenia. This study developed a series of new 4-benzoylpiperidine derivatives as GlyT1 inhibitors by bioisosteric replacement and mimicking of the pyridine ring of RG1678. Among the 4-benzoylpiperidine derivatives, 23q showed an IC50 of 30 nM. Preliminary optimization of the blood-brain barrier penetration led to the discovery of 3-(piperidin-4-yl)benzo[d]isoxazole derivatives. Both series showed good selectivity over GlyT2, D-1, D-2, D-3, 5-HT1A and 5-HT2A receptors. Moreover, behavioral testing showed 23q (40 mg kg(-1), intragastric) can inhibit the hyperlocomotion induced by acute treatment of phencyclidine, and improve the impaired negative and cognitive symptoms in chronic phencyclidine-induced C57BL/6J mice. An interesting finding showed that 3-(piperidin-4-yl)benzo[d]isoxazole was a privileged scaffold of atypical antipsychotic agents but exhibited high selectivity and potency as a GlyT1 inhibitor.
资助项目	National Nature Science Foundation of China[81402786] ; National Nature Science Foundation of China[81130023] ; National Basic Research Plan (973) of the Ministry of Science and Technology of China[2011CB5C4403] ; Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD)[00000000] ; Jiangsu Science and Technology Commission[BY2011131]
WOS关键词	GLYCINE TRANSPORTERS ; SCHIZOPHRENIA ; IDENTIFICATION ; DEFICITS
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000354212300059
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276733]
专题	药理学第二研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心药物化学研究室
通讯作者	Shen, Jianhua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Soochow Univ, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou 215006, Peoples R China; 3.Soochow Univ, Dept Pharmacol, Suzhou 215006, Peoples R China; 4.China Pharmaceut Univ, Nanjing 210009, Peoples R China
推荐引用方式 GB/T 7714	Liu, Yang,Guo, Lin,Duan, Hongliang,et al. Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors[J]. RSC ADVANCES,2015,5(51):40964-40977.
APA	Liu, Yang.,Guo, Lin.,Duan, Hongliang.,Zhang, Liming.,Jiang, Neng.,...&Shen, Jianhua.(2015).Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors.RSC ADVANCES,5(51),40964-40977.
MLA	Liu, Yang,et al."Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors".RSC ADVANCES 5.51(2015):40964-40977.