Discovery of pyrazole as C-terminus of selective BACE1 inhibitors

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• 作者：Yiquan Zou ; Lei Xu ; Wuyan Chen ; Yiping Zhu ; Tiantian Chen ; Yan Fu ; Li Li ; Lanping Ma ; Bing Xiong ; Xin Wang ; Jian Li ; Jianhua He ; Haiyan Zhang ; Yechun Xu ; Jia Li ; Jingkang Shen
• 关键词：Alzheimer's disease ; BACE1 ; C-terminus ; Click chemistry ; In situ screening assay ; Pyrazole
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：68
• 期：Complete
• 页码：270-283
• 全文大小：1786 K

文摘

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¦Â_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?¦ÌM) and compound 33 showed moderate inhibition effects on A¦Â 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.