Discovery of highly potent and selective orexin 1 receptor antagonists (1-SORAs) suitable for in vivo interrogation of orexin 1 receptor pharmacology

被引：13

作者：

Stump, Craig A. ^{[1
]}

Cooke, Andrew J. ^{[1
]}

Bruno, Joseph ^{[4
]}

Cabalu, Tamara D. ^{[3
]}

Gotter, Anthony L. ^{[2
]}

Harell, C. Meacham ^{[2
]}

Kuduk, Scott D. ^{[1
]}

McDonald, Terrence P. ^{[2
]}

O'Brien, Julie ^{[4
]}

Renger, John J. ^{[2
]}

Williams, Peter D. ^{[1
]}

Winrow, Christopher J. ^{[2
]}

Coleman, Paul J. ^{[1
]}

机构：

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

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

[3] Merck Res Labs, Pharmacokinet Pharmacodynam & Drug Metab, West Point, PA 19486 USA

[4] Merck Res Labs, Vitro Pharmacol, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 23期

关键词：

Selective orexin receptor antagonist (SORA); Dual orexin receptor antagonist (DORA); Orexin-1; Suvorexant; Filorexant; HUMAN NARCOLEPSY; SLEEP; INSOMNIA;

D O I：

10.1016/j.bmcl.2016.10.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with > 625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：5809 / 5814

页数：6

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