Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

被引：21

作者：

Mercer, Swati P. ^{[1
]}

Roecker, Anthony J. ^{[1
]}

Garson, Susan ^{[2
]}

Reiss, Duane R. ^{[2
]}

Harrell, C. Meacham ^{[2
]}

Murphy, Kathy L. ^{[2
]}

Bruno, Joseph G. ^{[4
]}

Bednar, Rodney A. ^{[4
]}

Lemaire, Wei ^{[2
]}

Cui, Donghui ^{[3
]}

Cabalu, Tamara D. ^{[3
]}

Tang, Cuyue ^{[3
]}

Prueksaritanont, Thomayant ^{[3
]}

Hartman, George D. ^{[1
]}

Young, Steven D. ^{[1
]}

Winrow, Christopher J. ^{[2
]}

Renger, John J. ^{[2
]}

Coleman, Paul J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Neurosci, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

[4] Merck Res Labs, West Point Facil Automat & Screening WP FAST, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 24期

关键词：

Orexin receptor antagonists; Selective orexin-2 receptor antagonists; Insomnia; Hypocretin; Rat sleep EEG; P-GLYCOPROTEIN; POTENT; SLEEP; PROMOTION;

D O I：

10.1016/j.bmcl.2013.10.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：6620 / 6624

页数：5

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