Substituted pyrrolidin-2-ones: Centrally acting orexin receptor antagonists promoting sleep. Part 2

被引：28

作者：

Sifferlen, Thierry ^{[1
]}

Boller, Amandine ^{[1
]}

Chardonneau, Audrey ^{[1
]}

Cottreel, Emmanuelle ^{[1
]}

Gatfield, John ^{[1
]}

Treiber, Alexander ^{[1
]}

Roch, Catherine ^{[1
]}

Jenck, Francois ^{[1
]}

Aissaoui, Hamed ^{[1
]}

Williams, Jodi T. ^{[1
]}

Brotschi, Christine ^{[1
]}

Heidmann, Bibia ^{[1
]}

Siegrist, Romain ^{[1
]}

Boss, Christoph ^{[1
]}

机构：

[1] Actel Pharmaceut Ltd, Drug Discovery & Preclin Res & Dev, CH-4123 Allschwil, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 09期

关键词：

Orexin receptors; Dual orexin receptor antagonists; Selective orexin-2 receptor antagonists; Sleep; CNS drug discovery; Metabolic stability; PHARMACOLOGICAL CHARACTERIZATION; P-GLYCOPROTEIN; DISCOVERY; DERIVATIVES; INSOMNIA; DISORDERS; POTENT; IDENTIFICATION; ADDICTION; 2-SORA;

D O I：

10.1016/j.bmcl.2015.03.035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the gamma-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：1884 / 1891

页数：8

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