title: Discovery of pyrazole as C-terminus of selective BACE1 inhibitors.
abstract: 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 Aβ1-40 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 μM) and compound 33 showed moderate inhibition effects on Aβ 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
authors.forename: Yiquan
authors.initials: Y
authors.lastname: Zou
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Lanping
authors.initials: L
authors.lastname: Ma
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's disease; BACE1; C-terminus; Click chemistry; DCM; DIPEA; DMF; EDCl; EtOAc; HOBt; In situ screening assay; N,N-diisopropylethylamine; N,N-dimethylformamide; N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; N-hydroxybenzotriazole; Pyrazole; THF; dichloromethane; ethyl acetate; tetrahydrofuran