Discovery of pyrazole as C-terminus of selective BACE1 inhibitors

doi:10.1016/j.ejmech.2013.06.027

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	Discovery of pyrazole as C-terminus of selective BACE1 inhibitors
	Zou, Yiquan 2; Xu, Lei 1; Chen, Wuyan 2; Zhu, Yiping 2; Chen, Tiantian 2; Fu, Yan 2; Li, Li 2; Ma, Lanping2 ; Xiong, Bing2 ; Wang, Xin2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2013-10
卷号	68 页码:270-283
关键词	Alzheimer's disease BACE1 C-terminus Click chemistry In situ screening assay Pyrazole
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2013.06.027
文献子类	Article
英文摘要	We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous A beta(1-40) production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50 = 0.025 mu M) and compound 33 showed moderate inhibition effects on A beta production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs. (C) 2013 Elsevier Masson SAS. All rights reserved.
资助项目	National S&T Major Projects "Key New Drug Creation and Manufacturing Program" of China[2009ZX09301-001] ; National S&T Major Projects "Key New Drug Creation and Manufacturing Program" of China[2009ZX09501-010] ; "100 Talents Project" of CAS[00000000] ; Shanghai Pujiang Program[10PJ1412000] ; National Natural Science Foundation of China[21172233]
WOS关键词	BETA-SECRETASE INHIBITORS ; ALZHEIMERS-DISEASE ; CLICK-CHEMISTRY ; THYMOCYTE DEVELOPMENT ; AMYLOID HYPOTHESIS ; CASCADE HYPOTHESIS ; GENERATION ; DESIGN ; DIFFERENTIATION ; THERAPEUTICS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000326902300029
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277432]
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化学研究室国家新药筛选中心
通讯作者	Zhang, Haiyan
作者单位	1.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 Sci, Shanghai Inst Appl Phys, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zou, Yiquan,Xu, Lei,Chen, Wuyan,et al. Discovery of pyrazole as C-terminus of selective BACE1 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2013,68:270-283.
APA	Zou, Yiquan.,Xu, Lei.,Chen, Wuyan.,Zhu, Yiping.,Chen, Tiantian.,...&Shen, Jingkang.(2013).Discovery of pyrazole as C-terminus of selective BACE1 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,68,270-283.
MLA	Zou, Yiquan,et al."Discovery of pyrazole as C-terminus of selective BACE1 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 68(2013):270-283.