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
收藏
页码：1884 / 1891
页数：8
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