Design and synthesis of potent β-secretase (BACE1) inhibitors with P1′ carboxylic acid bioisosteres

被引：63

作者：

Kimura, T

Hamada, Y

Stochaj, M

Ikari, H

Nagamine, A

Abdel-Rahman, H

Igawa, N

Hidaka, K

Nguyen, JT

Saito, K

Hayashi, Y

Kiso, Y ^{[1
]}

机构：

[1] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Dept Med Chem, Yamashina Ku, Kyoto 6078412, Japan

[2] Kyoto Pharmaceut Univ, 21st Century COE Program, Lab Proteom Sci, Yamashina Ku, Kyoto 6078412, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 09期

基金：

日本学术振兴会;

关键词：

Alzheimer's disease; BACE1; inhibitor; beta-secretase; bioisostere;

D O I：

10.1016/j.bmcl.2006.01.108

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P-4 position of KMI-260 and KMI-360, respectively, with a H-1-tetrazole-5-carbonyl DAP (L-alpha,beta-diaminopropionic acid) residue. At the P-l' position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood-brain barrier. Herein, we report BACE1 inhibitors with P-l' carboxylic acid bioisosteres in order to develop practical anti-Alzheimer's disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50 = 4.8 nM) and KM1-684 (IC50 = 1.2 nM), exhibited significantly potent BACE1 inhibitory activities. (C) 2006 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2380 / 2386

页数：7

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