Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors
Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors
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DOI：
10.1021/jm901414e
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发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Robichaud, Albert J.
中科院分区：
文献类型：
--
作者：
Malamas, Michael S.;Erdei, Jim;Robichaud, Albert J.
报道了小分子氨基乙内酰脲作为有效的和选择性的人β-分泌酶抑制剂的鉴定。这些类似物表现出对BACE 1的低纳摩尔效力，在基于细胞的（ELISA）测定中显示出相当的活性，并且表现出对其他结构上相关的乙酰基蛋白酶BACE 2、组织蛋白酶D、肾素和胃蛋白酶的> 100倍的选择性。基于BACE 1活性位点中HTS-hit 2的共晶结构，并通过使用基于结构的药物设计方法，我们系统地探索了BACE 1酶的相对较大的结合口袋，并确定了配体和蛋白质之间的关键相互作用，这些相互作用有助于亲和力。其中一种更有效的化合物（S）-55对BACE 1的IC 50值为10 nM，并在ELISA试验中表现出相当的细胞活性（EC 50 = 20 nM）。在Tg 2576小鼠中，100 mg/kg的（S）-55急性口服给药导致血浆A β（40）在8 h时降低69%（p < 0.001）。
The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate > 100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC50 value for BACE1 of 10 nM and exhibited comparable cellular activity (EC50 = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).