BACE1 inhibitors:: Optimization by replacing the P1′ residue with non-acidic moiety
BACE1 inhibitors:: Optimization by replacing the P1′ residue with non-acidic moiety
复制标题
DOI：
10.1016/j.bmcl.2008.01.058
复制
发表时间：
2008-03-01
影响因子：
2.7
通讯作者：
Kiso, Yoshiaki
中科院分区：
文献类型：
--
作者：
Hamada, Yoshio;Abdel-Rahman, Hamdy;Kiso, Yoshiaki
最近，我们报道了有效的BACE1抑制剂KMI-429， -684和-574具有羟基甲基羰基同分异构体作为底物过渡态模拟物。这些抑制剂在酶和细胞实验中显示出有效的抑制活性，特别是KMI-429被证实能显著抑制体内A β的产生。然而，kmi -化合物的P-4和P-1'位置的酸性部分被认为不利于血脑屏障的膜通透性。在这里，我们用其他氢键受体基团取代了P-4位置的酸性部分，这些抑制剂在培养细胞中表现出更好的BACE1抑制活性。在这项研究中，我们用非酸性和低分子大小的部分取代了P-1'位置的酸性部分。(c) 2008 Elsevier Ltd.版权所有。
Recently, we reported potent BACE1 inhibitors KMI-429, -684, and -574 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays, especially, KMI-429 was confirmed to significantly inhibit A beta production in vivo. However, acidic moieties at the P-4 and P-1' positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P-4 position with other hydrogen bond acceptor groups, and these inhibitors exhibited improved BACE1 inhibitory activities in cultured cells. In this study, we replaced the acidic moieties at the P-1' position with non-acidic and low molecular sized moieties. (c) 2008 Elsevier Ltd. All rights reserved.