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
收藏
页码：211 / 215
页数：5
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