Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay

doi:10.1038/aps.2013.25

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 国家新药筛选中心

	Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay
	Li, Qun-yi 1,2; Xu, Ming-kai 1,2; Liu, Gang 3; Christoffersen, Claus Tornby 4; Wang, Ming-wei1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2013-08
卷号	34 期号:8 页码:1116-1120
关键词	phosphodiesterase 10 (PDE10) papaverine high-throughput screening psychosis
ISSN号	1671-4083
DOI	10.1038/aps.2013.25
文献子类	Article
英文摘要	Aim: To develop a homogeneous assay for high-throughput screening (HTS) of inhibitors of phosphodiesterase 10 (PDE10). Methods: Purified human PDE10 enzyme derived from E coli, [H-3]-cAMP and yttrium silicate microbeads were used to develop an HTS assay based on the scintillation proximity assay (SPA) technology. This method was applied to a large-scale screening campaign against a diverse compound library and subsequent confirmation studies. Preliminary structure-activity relationship (SAR) studies were initiated through limited structural modifications of the hits. Results: The IC50 value of the control compound (papaverine) assessed with the SPA approach was comparable and consistent with that reported in the literature. Signal to background (S/B) ratio and Z' factor of the assay system were evaluated to be 5.24 and 0.71, respectively. In an HTS campaign of 71 360 synthetic and natural compounds, 67 hits displayed reproducible PDE10 inhibition, of which, 8 were chosen as the scaffold for structural modifications and subsequent SAR analysis. Conclusion: The homogeneous PDE10 SPA assay is an efficient and robust tool to screen potential PDE10 inhibitors. Preliminary SAR studies suggest that potent PDE10 inhibitors could be identified and developed through this strategy.
资助项目	H Lundbeck A/S[00000000] ; Ministry of Science and Technology of China[2009ZX09302-001] ; Ministry of Science and Technology of China[2012ZX09304011] ; Ministry of Science and Technology of China[2013ZX09507002] ; Shanghai Science and Technology Development Fund[11DZ2292200]
WOS关键词	PHOSPHODIESTERASE 10A INHIBITORS ; SCHIZOPHRENIA ; SYMPTOMS ; DISEASE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4896749
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000322709400017
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277520]
专题	国家新药筛选中心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
通讯作者	Wang, Ming-wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China; 4.H Lundbeck & Co AS, DK-2500 Copenhagen, Denmark
推荐引用方式 GB/T 7714	Li, Qun-yi,Xu, Ming-kai,Liu, Gang,et al. Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay[J]. ACTA PHARMACOLOGICA SINICA,2013,34(8):1116-1120.
APA	Li, Qun-yi,Xu, Ming-kai,Liu, Gang,Christoffersen, Claus Tornby,&Wang, Ming-wei.(2013).Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay.ACTA PHARMACOLOGICA SINICA,34(8),1116-1120.
MLA	Li, Qun-yi,et al."Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay".ACTA PHARMACOLOGICA SINICA 34.8(2013):1116-1120.