Design and synthesis of highly active Alzheimer's β-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability

被引：92

作者：

Kimura, T

Shuto, D

Hamada, Y

Igawa, N

Kasai, S

Liu, P

Hidaka, K

Hamada, T

Hayashi, Y

Kiso, Y ^{[1
]}

机构：

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

[2] Kyoto Pharmaceut Univ, Century COE Program 21st, Yamashima Ku, Kyoto 6078412, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 01期

关键词：

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

D O I：

10.1016/j.bmcl.2004.09.090

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 BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a beta-N-oxalyl-DAP (L-alpha,beta-diaminopropionyl) residue at the P-4 position. The beta-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to alpha-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：211 / 215

页数：5

共 30 条

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