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Molecules 2013, 18(3), 3577-3594; doi:10.3390/molecules18033577
Article

Design, Synthesis and Evaluation of 3-(2-Aminoheterocycle)-4-benzyloxyphenylbenzamide Derivatives as BACE-1 Inhibitors

1, 1, 1, 2, 2, 1,3, 4, 4, 1 and 1,*
1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China 2 The National Center for Drug Screening, Shanghai 201203, China 3 Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China 4 Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
* Author to whom correspondence should be addressed.
Received: 17 February 2013 / Revised: 15 March 2013 / Accepted: 18 March 2013 / Published: 20 March 2013
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.
Keywords: BACE-1 inhibitor; 2-amino-6H-1,3,4-thiadizine; blood-brain barrier permeability BACE-1 inhibitor; 2-amino-6H-1,3,4-thiadizine; blood-brain barrier permeability
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Shangguan, S.; Wang, F.; Liao, Y.; Yu, H.; Li, J.; Huang, W.; Hu, H.; Yu, L.; Hu, Y.; Sheng, R. Design, Synthesis and Evaluation of 3-(2-Aminoheterocycle)-4-benzyloxyphenylbenzamide Derivatives as BACE-1 Inhibitors. Molecules 2013, 18, 3577-3594.

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