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
Asai, M
Hattori, C
Iwata, N
Saido, TC
Sasagawa, N
Szabó, B
Hashimoto, Y
Maruyama, K
Tanuma, S
Kiso, Y
Ishiura, S
[J]. 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
Bruinzeel, W
Yon, J
Giovannelli, S
Masure, S
[J]. PROTEIN EXPRESSION AND PURIFICATION, 2002, 26 (01) : 139 - 148
[3] The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer's disease
Catalano, Susan M.
Dodson, Elizabeth C.
Henze, Darrell A.
Joyce, Joseph G.
Krafft, Grant A.
Kinney, Gene G.
[J]. CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2006, 6 (06) : 597 - 608
[4] In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors
Chang, WP
Koelsch, G
Wong, S
Downs, D
Da, HN
Weerasena, V
Gordon, B
Devasamudram, T
Bilcer, G
Ghosh, AK
Tang, J
[J]. JOURNAL OF NEUROCHEMISTRY, 2004, 89 (06) : 1409 - 1416
[5] Tau therapeutic strategies for the treatment of Alzheimer's disease
Churcher, Ian
[J]. 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
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
[J]. 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)
Ghosh, AK
Shin, DW
Downs, D
Koelsch, G
Lin, XL
Ermolieff, J
Tang, J
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (14) : 3522 - 3523
[10] A century of Alzheimer's disease
Goedert, Michel
Spillantini, Maria Grazia
[J]. SCIENCE, 2006, 314 (5800) : 777 - 781

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