Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Issue 24 (15th December 2019)

• Record Type: Journal Article
• Authors: Fan, Tian-Yuan; Wu, Wen-Yu; Yu, Shao-Peng; Zhong, Yue; Zhao, Chao; Chen, Min; Li, He-Min; Li, Nian-Guang; Chen, Zhi; Chen, Sai; Sun, Zhi-Hui; Duan, Jin-Ao; Shi, Zhi-Hao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 24(2019)
• Publication Date: 2019-12-15
• Subjects: Alzheimer's disease -- BACE1 inhibitors -- Design and synthesis -- Iminopyrimidinone scaffold -- Structure–activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126772
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Inhibition of β -site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain β -amyloid (Aβ) peptide's formation is a potential effective approach to treat Alzheimer's disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 μM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 μM, logP = 2.49).