Discovery of a novel series of Notch-sparing γ-secretase inhibitors

被引：20

作者：

Kreft, Anthony ^{[1
]}

Harrison, Boyd ^{[1
]}

Aschmies, Suzan ^{[2
]}

Atchison, Kevin ^{[2
]}

Casebier, David ^{[4
]}

Cole, Derek C. ^{[1
]}

Diamantidis, George ^{[1
]}

Ellingboe, John ^{[1
]}

Hauze, Diane ^{[1
]}

Hu, Yun ^{[2
]}

Huryn, Donna ^{[1
]}

Jin, Mei ^{[2
]}

Kubrak, Dennis ^{[1
]}

Lu, Peimin ^{[2
]}

Lundquist, Joseph ^{[1
]}

Mann, Charles ^{[1
]}

Martone, Robert ^{[2
]}

Moore, William ^{[4
]}

Oganesian, Aram ^{[3
]}

Porte, Alex ^{[1
]}

Riddell, Dave R. ^{[2
]}

Sonnenberg-Reines, June ^{[2
]}

Stock, Joseph R. ^{[1
]}

Sun, Shaiu-Ching ^{[2
]}

Wagner, Erik ^{[2
]}

Woller, Kevin ^{[4
]}

Xu, Zheng ^{[2
]}

Zhou, Hua ^{[2
]}

Jacobsen, J. Steven ^{[2
]}

机构：

[1] Wyeth Ayerst Res, Chem & Screening Sci, Princeton, NJ 08543 USA

[2] Wyeth Ayerst Res, Discovery Neurosci, Princeton, NJ 08543 USA

[3] Wyeth Ayerst Res, Drug Safety & Metab, Collegeville, PA 19426 USA

[4] ArQule Inc, Woburn, MA 01801 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 14期

基金：

美国国家卫生研究院;

关键词：

Alzheimer's disease; gamma-secretase; Notch; amyloid; protease inhibitor;

D O I：

10.1016/j.bmcl.2008.05.064

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4232 / 4236

页数：5

共 38 条

[21] Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores [J].

Lazarov, VK ;

Fraering, PC ;

Ye, W ;

Wolfe, MS ;

Selkoe, DJ ;

Li, HL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (18) :6889-6894

[22] Selective modulation of Aβ42 production in Alzheimer's disease:: Non-steroidal anti-inflammatory drugs and beyond [J].

Leuchtenberger, Stefanie ;

Beher, Dirk ;

Weggen, Sascha .

CURRENT PHARMACEUTICAL DESIGN, 2006, 12 (33) :4337-4355

[23] γ-Secretase:: a complex target for Alzheimer's disease [J].

Lundkvist, Johan ;

Naslund, Jan .

CURRENT OPINION IN PHARMACOLOGY, 2007, 7 (01) :112-118

[24] Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation [J].

Milano, J ;

McKay, J ;

Dagenais, C ;

Foster-Brown, L ;

Pognan, F ;

Gadient, R ;

Jacobs, RT ;

Zacco, A ;

Greenberg, B ;

Ciaccio, PJ .

TOXICOLOGICAL SCIENCES, 2004, 82 (01) :341-358

[25] Three-dimensional structure of the γ-secretase complex [J].

Ogura, T ;

Mio, K ;

Hayashi, I ;

Miyashita, H ;

Fukuda, R ;

Kopan, R ;

Kodama, T ;

Hamakubo, T ;

Iwastubo, T ;

Tomita, T ;

Sato, C .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2006, 343 (02) :525-534

[26] Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796):: A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's disease [J].

Prasad, C. V. C. ;

Zheng, Ming ;

Vig, Shikha ;

Bergstrom, Carl ;

Smith, David W. ;

Gao, Qi ;

Yeola, Suresh ;

Polson, Craig T. ;

Corsa, Jason A. ;

Guss, Valerie L. ;

Loo, Alice ;

Wang, Jian ;

Sleczka, Bogdan G. ;

Dangler, Charles ;

Robertson, Barbara J. ;

Hendrick, Joseph P. ;

Roberts, Susan B. ;

Barten, Donna M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (14) :4006-4011

[27] Inhibitors and modulators of β- and γ-secretase [J].

Schmidt, Boris ;

Baumann, Stefanie ;

Braun, Hannes A. ;

Larbig, Gregor .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2006, 6 (04) :377-392

[28] Alzheimer disease: Mechanistic understanding predicts novel therapies [J].

Selkoe, DJ .

ANNALS OF INTERNAL MEDICINE, 2004, 140 (08) :627-638

[29] Notch signaling, γ-secretase inhibitors, and cancer therapy [J].

Shih, Ie-Ming ;

Wang, Tian-Li .

CANCER RESEARCH, 2007, 67 (05) :1879-1882

[30] Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease [J].

Siemers, ER ;

Quinn, JF ;

Kaye, J ;

Farlow, MR ;

Porsteinsson, A ;

Tariot, P ;

Zoulnouni, P ;

Galvin, JE ;

Holtzman, DM ;

Knopman, DS ;

Satterwhite, J ;

Gonzales, C ;

Dean, RA ;

May, PC .

NEUROLOGY, 2006, 66 (04) :602-604

← 1 2 3 4 →