CAS OpenIR  > 中科院上海应用物理研究所2011-2020年
Discovery of pyrazole as C-terminus of selective BACE1 inhibitors
Zou, Yiquan; Xu, Lei; Chen, Wuyan; Zhu, Yiping; Chen, Tiantian; Fu, Yan; Li, Li; Ma, Lanping; Xiong, Bing; Wang, Xin; Li, Jian; He, Jianhua; Zhang, Haiyan; Xu, Yechun; Li, Jia; Shen, Jingkang
ISSN0223-5234; 1768-3254
AbstractWe 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.
Indexed BySCI
Funding Project应物所项目组
WOS IDWOS:000326902300029
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Cited Times:19[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
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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:CONCATENATE(Sheet1!I89,-Sheet1!J89).
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,CONCATENATE(Sheet1!I89,-Sheet1!J89).
MLA Zou, Yiquan,et al."Discovery of pyrazole as C-terminus of selective BACE1 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 68(2013):CONCATENATE(Sheet1!I89,-Sheet1!J89).
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