2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme):: Use of structure based design to convert a micromolar hit into a nanomolar lead

被引：127

作者：

Baxter, Ellen W. ^{[1
]}

Conway, Kelly A. ^{[1
]}

Kennis, Ludo ^{[1
]}

Bischoff, Francois ^{[1
]}

Mercken, Marc H. ^{[1
]}

De Winter, Hans L. ^{[1
]}

Reynolds, Charles H. ^{[1
]}

Tounge, Brett A. ^{[1
]}

Luo, Chi ^{[1
]}

Scott, Malcolm K. ^{[1
]}

Huang, Yifang ^{[1
]}

Braeken, Mirielle ^{[1
]}

Pieters, Sere M. A. ^{[1
]}

Berthelot, Didier J. C. ^{[1
]}

Masure, Stefan ^{[1
]}

Bruinzeel, Wouter D. ^{[1
]}

Jordan, Alfonzo D. ^{[1
]}

Parker, Michael H. ^{[1
]}

Boyd, Robert E. ^{[1
]}

Qu, Junya ^{[1
]}

Alexander, Richard S. ^{[1
]}

Brenneman, Douglas E. ^{[1
]}

Reitz, Allen B. ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 18期

关键词：

X-RAY CRYSTALLOGRAPHY; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; SECRETASE BACE-1; IN-VIVO; EXPRESSION; DISCOVERY; LIGANDS; POTENT; BRAIN;

D O I：

10.1021/jm0705408

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 mu M to 11 nM K-i) by substitution into the unoccupied S-1 ' pocket.

引用

页码：4261 / 4264

页数：4

共 30 条

[1] The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice [J].

Asai, M ;

Hattori, C ;

Iwata, N ;

Saido, TC ;

Sasagawa, N ;

Szabó, B ;

Hashimoto, Y ;

Maruyama, K ;

Tanuma, S ;

Kiso, Y ;

Ishiura, S .

JOURNAL OF NEUROCHEMISTRY, 2006, 96 (02) :533-540

[2] Recombinant insect cell expression and purification of human β-secretase (BACE-1) for X-ray crystallography [J].

Bruinzeel, W ;

Yon, J ;

Giovannelli, S ;

Masure, S .

PROTEIN EXPRESSION AND PURIFICATION, 2002, 26 (01) :139-148

[3] The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer's disease [J].

Catalano, Susan M. ;

Dodson, Elizabeth C. ;

Henze, Darrell A. ;

Joyce, Joseph G. ;

Krafft, Grant A. ;

Kinney, Gene G. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2006, 6 (06) :597-608

[4] In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors [J].

Chang, WP ;

Koelsch, G ;

Wong, S ;

Downs, D ;

Da, HN ;

Weerasena, V ;

Gordon, B ;

Devasamudram, T ;

Bilcer, G ;

Ghosh, AK ;

Tang, J .

JOURNAL OF NEUROCHEMISTRY, 2004, 89 (06) :1409-1416

[5] Tau therapeutic strategies for the treatment of Alzheimer's disease [J].

Churcher, Ian .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2006, 6 (06) :579-595

[6] 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

[7]

DEPEREZ RMB, 1986, J ORG CHEM, V51, P2039

[8]

Freyne E.J.E., 1990, European Patent, Patent No. 371564

[9] Design of potent inhibitors for human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Shin, DW ;

Downs, D ;

Koelsch, G ;

Lin, XL ;

Ermolieff, J ;

Tang, J .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (14) :3522-3523

[10] A century of Alzheimer's disease [J].

Goedert, Michel ;

Spillantini, Maria Grazia .

SCIENCE, 2006, 314 (5800) :777-781

← 1 2 3 →