Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors

被引：13

作者：

Chirapu, Srinivas Reddy ^{[1
]}

Pachaiyappan, Boobalan ^{[1
]}

Nural, Hikmet F. ^{[2
]}

Cheng, Xin ^{[2
]}

Yuan, Hongbin ^{[1
]}

Lankin, David C. ^{[1
]}

Abdul-Hay, Samer O. ^{[1
]}

Thatcher, Gregory R. J. ^{[1
]}

Shen, Yong ^{[2
]}

Kozikowski, Alan P. ^{[1
]}

Petukhov, Pavel A. ^{[1
]}

机构：

[1] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA

[2] Sun Hlth Inst, Haldeman Lab Mol & Cellular Neurobiol, Sun City, AZ 85351 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 01期

关键词：

Alzheimer; BACE1; Aspartic protease; Computer-aided molecular design; AMYLOID PRECURSOR PROTEIN; DISEASE BETA-SECRETASE; ALZHEIMERS-DISEASE; PROTONATION STATES; POTENT INHIBITORS; ASPARTYL PROTEASE; DESIGN; APP; METATHESIS; SURFACE;

D O I：

10.1016/j.bmcl.2008.10.096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of transition state analogues of beta-secretases 1 and 2 ( BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of A beta 40 production in N2a cells stably transfected with Swedish human APP. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：264 / 274

页数：11

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