2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies

Eur J Med Chem. 2017 Sep 8:137:462-475. doi: 10.1016/j.ejmech.2017.06.020.

Gang Yan ¹, Lina Hao ¹, Yan Niu ², Wenjie Huang ¹, Wei Wang ¹, Fengrong Xu ¹, Lei Liang ¹, Chao Wang ¹, Hongwei Jin ³, Ping Xu ⁴

Affiliations

1 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
2 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Electronic address: yanniu@bjmu.edu.cn.
3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
4 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Electronic address: pingxu@bjmu.edu.cn.

PMID: 28624701 DOI: 10.1016/j.ejmech.2017.06.020

Abstract

In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives were developed as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (K_D) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC₅₀ = 4.6 μM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization.

Keywords

Alzheimer's disease; BACE-1 inhibitors; BBB; Docking study; PAMPA; Permeability; Surface Plasmon Resonance (SPR).

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