Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators

被引：53

作者：

Bischoff, Francois ^{[1
]}

Berthelot, Didier ^{[1
]}

De Cleyn, Michel ^{[1
]}

Macdonald, Gregor ^{[1
]}

Minne, Garrett ^{[1
]}

Oehlrich, Daniel ^{[1
]}

Pieters, Serge ^{[1
]}

Surkyn, Michel ^{[1
]}

Trabanco, Andres A. ^{[1
]}

Tresadern, Gary ^{[1
]}

Van Brandt, Sven ^{[1
]}

Velter, Ingrid ^{[1
]}

Zaja, Mirko ^{[1
]}

Borghys, Herman ^{[1
]}

Masungi, Chantal ^{[1
]}

Mercken, Marc ^{[1
]}

Gijsen, Harrie J. M. ^{[1
]}

机构：

[1] Pharmaceut Co Johnson & Johnson, Janssen Res & Dev, Beerse, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 21期

关键词：

ALZHEIMERS-DISEASE; MOUSE MODEL; BETA; INHIBITORS; PROTEIN; IDENTIFICATION; VALIDATION; EVOLUTION; DISCOVERY;

D O I：

10.1021/jm201710f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design and the synthesis of several chemical subclasses of imidazole containing gamma-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted, in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical gamma-secretase modulatory profile by lowering A beta 42 and A beta 40 levels combined with an especially pronounced increase in A beta 38 and A beta 37 levels while leaving the total levels of amyloid peptides unchanged.

引用

页码：9089 / 9106

页数：18

共 63 条

[1] Selective modulation of amyloid-β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels [J].

Abdul-Hay, Samer O. ;

Edirisinghe, Praneeth ;

Thatcher, Gregory R. J. .

JOURNAL OF NEUROCHEMISTRY, 2009, 111 (03) :683-695

[2]

[Anonymous], 2010, MOL OP ENV 2010 10 M

[3]

BAUMANN S, 2008, MED CHEM ALZHEIMERS, P193

[4] Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s [J].

Berchtold, NC ;

Cotman, CW .

NEUROBIOLOGY OF AGING, 1998, 19 (03) :173-189

[5]

Bergmans B. A., 2010, NEUROLOGY, V9, P215

[6]

Bischoff F. P., 2011, 242 ACS NAT M DENV C

[7] A Canine Model to Evaluate Efficacy and Safety of γ-Secretase Inhibitors and Modulators [J].

Borghys, Herman ;

Tuefferd, Marianne ;

Van Broeck, Bianca ;

Clessens, Ellen ;

Dillen, Lieve ;

Cools, Willy ;

Vinken, Petra ;

Straetemans, Roel ;

De Ridder, Filip ;

Gijsen, Harrie ;

Mercken, Marc .

JOURNAL OF ALZHEIMERS DISEASE, 2012, 28 (04) :809-822

[8] The mechanism of γ-Secretase dysfunction in familial Alzheimer disease [J].

Chavez-Gutierrez, Lucia ;

Bammens, Leen ;

Benilova, Iryna ;

Vandersteen, Annelies ;

Benurwar, Manasi ;

Borgers, Marianne ;

Lismont, Sam ;

Zhou, Lujia ;

Van Cleynenbreugel, Simon ;

Esselmann, Hermann ;

Wiltfang, Jens ;

Serneels, Lutgarde ;

Karran, Eric ;

Gijsen, Harrie ;

Schymkowitz, Joost ;

Rousseau, Frederic ;

Broersen, Kerensa ;

De Strooper, Bart .

EMBO JOURNAL, 2012, 31 (10) :2261-2274

[9]

Cheng S, 2004, Patent No. [WO2004110350, 2004110350]

[10] Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice [J].

Citron, M ;

Westaway, D ;

Xia, WM ;

Carlson, G ;

Diehl, T ;

Levesque, G ;

JohnsonWood, K ;

Lee, M ;

Seubert, P ;

Davis, A ;

Kholodenko, D ;

Motter, R ;

Sherrington, R ;

Perry, B ;

Yao, H ;

Strome, R ;

Lieberburg, I ;

Rommens, J ;

Kim, S ;

Schenk, D ;

Fraser, P ;

Hyslop, PS ;

Selkoe, DJ .

NATURE MEDICINE, 1997, 3 (01) :67-72

← 1 2 3 4 5 6 7 →