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

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