Acylguanidine inhibitors of β-secretase:: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets

被引：56

作者：

Cole, Derek C. ^{[1
]}

Stock, Joseph R. ^{[1
]}

Chopra, Rajiv ^{[2
]}

Cowling, Rebecca ^{[1
]}

Ellingboe, John W. ^{[1
]}

Fan, Kristi Y. ^{[3
]}

Harrison, Boyd L. ^{[3
]}

Hu, Yuri ^{[3
]}

Jacobsen, Steve ^{[3
]}

Jennings, Lee D. ^{[1
]}

Jin, Guixian ^{[1
]}

Lohse, Peter A. ^{[4
]}

Malamas, Michael S. ^{[3
]}

Manas, Eric S. ^{[5
]}

Moore, William J. ^{[5
]}

O'Donnell, Mary-Margaret ^{[4
]}

Olland, Andrea M. ^{[2
]}

Robichaud, Albert J. ^{[3
]}

Svenson, Kristine ^{[2
]}

Wu, JunJun ^{[2
]}

Wagner, Eric ^{[3
]}

Bard, Jonathan ^{[3
]}

机构：

[1] Wyeth Ayerst Res, Pearl River, NY 10965 USA

[2] Wyeth Ayerst Res, Cambridge, MA 02140 USA

[3] Wyeth Ayerst Res, Monmouth Jct, NJ 08852 USA

[4] ArQule, Woburn, MA 01801 USA

[5] Wyeth Ayerst Res, Collegeville, PA 19426 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 03期

关键词：

BACE-1; beta-secretase; inhibitor; acylguanidine;

D O I：

10.1016/j.bmcl.2007.12.010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S-1 and S-2' pockets leading to submicromolar BACE-1 inhibitors. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1063 / 1066

页数：4

共 13 条

[1] Insights from modeling the tertiary structure of human BACE2 [J].

Chou, KC .

JOURNAL OF PROTEOME RESEARCH, 2004, 3 (05) :1069-1072

[2] Acylguanidines as small-molecule β-secretase inhibitors [J].

Cole, Derek C. ;

Manas, Eric S. ;

Stock, Joseph R. ;

Condon, Jeffrey S. ;

Jennings, Lee D. ;

Aulabaugh, Ann ;

Chopra, Rajiv ;

Cowling, Rebecca ;

Ellingboe, John W. ;

Fan, Kristi Y. ;

Harrison, Boyd L. ;

Hu, Yun ;

Jacobsen, Steve ;

Jin, Guixan ;

Lin, Laura ;

Lovering, Frank E. ;

Malamas, Michael S. ;

Stahl, Mark L. ;

Strand, James ;

Sukhdeo, Mohani N. ;

Svenson, Kristine ;

Turner, M. James ;

Wagner, Erik ;

Wu, Junjun ;

Zhou, Ping ;

Bard, Jonathan .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (21) :6158-6161

[3] Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase [J].

Congreve, Miles ;

Aharony, David ;

Albert, Jeffrey ;

Callaghan, Owen ;

Campbell, James ;

Carr, Robin A. E. ;

Chessari, Gianni ;

Cowan, Suzanna ;

Edwards, Philip D. ;

Frederickson, Martyn ;

McMenamin, Rachel ;

Murray, Christopher W. ;

Patel, Sahil ;

Wallis, Nicola .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (06) :1124-1132

[4]

Durham TB, 2006, CURR OPIN DRUG DISC, V9, P776

[5] Memapsin 2 (Beta-Secretase) inhibitor drug, between fantasy and reality [J].

Ghosh, Arun K. ;

Bilcer, Geoffrey ;

Hong, Lin ;

Koelsch, Gerald ;

Tang, Jordan .

CURRENT ALZHEIMER RESEARCH, 2007, 4 (04) :418-422

[6]

Hills ID, 2007, CURR OPIN DRUG DISC, V10, P383

[7] Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor [J].

Hong, L ;

Koelsch, G ;

Lin, XL ;

Wu, SL ;

Terzyan, S ;

Ghosh, AK ;

Zhang, XC ;

Tang, J .

SCIENCE, 2000, 290 (5489) :150-153

[8] Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 [J].

Li, YM ;

Xu, M ;

Lai, MT ;

Huang, Q ;

Castro, JL ;

DiMuzio-Mower, J ;

Harrison, T ;

Lellis, C ;

Nadin, JL ;

Neduvelil, JG ;

Sardana, MK ;

Shearman, MS ;

Smith, AL ;

Shi, XP ;

Yin, KC ;

Shafer, JA ;

Gardell, SJ .

NATURE, 2000, 405 (6787) :689-694

[9] Application of fragment screening by X-ray crystallography to β-secretase [J].

Murray, Christopher W. ;

Callaghan, Owen ;

Chessari, Gianni ;

Cleasby, Anne ;

Congreve, Miles ;

Frederickson, Martyn ;

Hartshorn, Michael J. ;

McMenamin, Rachel ;

Patel, Sahil ;

Wallis, Nicola .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (06) :1116-1123

[10]

Nevar NM, 2000, SYNTHESIS-STUTTGART, P1259

← 1 2 →