Design, Synthesis and Evaluation of 3-(2-Aminoheterocycle)-4-benzyloxyphenylbenzamide Derivatives as BACE-1 Inhibitors
Design, Synthesis and Evaluation of 3-(2-Aminoheterocycle)-4-benzyloxyphenylbenzamide Derivatives as BACE-1 Inhibitors
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DOI：
10.3390/molecules18033577
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发表时间：
2013-03-01
期刊：
影响因子：
4.6
通讯作者：
Sheng, Rong
中科院分区：
文献类型：
--
作者：
Shangguan, Shihao;Wang, Fei;Sheng, Rong
设计、合成了3个系列的3-（2-氨基杂环）-4-苄氧基苯基苯甲酰胺类化合物：2-氨基恶唑、2-氨基噻唑和2-氨基-6H-1，3，4-噻二嗪类化合物，并对其进行了活性评价。初步构效关系表明，2-氨基-6H-1，3，4-噻二嗪和α-萘基的存在有利于BACE-1的抑制。在合成的化合物中，5e表现出最有效的BACE-1抑制活性，IC 50值为9.9 μ M，并且在Madin-Darby肾细胞系（MDCK）和Madin-Darby犬肾多药耐药1（MDCK-MDR 1）模型中表现出高脑摄取潜力。
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 beta-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and a-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 mu M 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.