Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia

被引：324

作者：

Cox, Christopher D. ^{[1
]}

Breslin, Michael J. ^{[1
]}

Whitman, David B. ^{[1
]}

Schreier, John D. ^{[1
]}

McGaughey, Georgia B. ^{[2
]}

Bogusky, Michael J. ^{[1
]}

Roecker, Anthony J. ^{[1
]}

Mercer, Swati P. ^{[1
]}

Bednar, Rodney A. ^{[3
]}

Lemaire, Wei ^{[3
]}

Bruno, Joseph G. ^{[3
]}

Reiss, Duane R. ^{[4
]}

Harrell, C. Meacham ^{[4
]}

Murphy, Kathy L. ^{[4
]}

Garson, Susan L. ^{[4
]}

Doran, Scott M. ^{[4
]}

Prueksaritanont, Thomayant ^{[5
]}

Anderson, Wayne B. ^{[5
]}

Tang, Cuyue ^{[5
]}

Roller, Shane ^{[5
]}

Cabalu, Tamara D. ^{[5
]}

Cui, Donahui ^{[5
]}

Hartman, George D. ^{[1
]}

Young, Steven D. ^{[1
]}

Koblan, Ken S. ^{[4
]}

Winrow, Christopher J. ^{[4
]}

Renger, John J. ^{[4
]}

Coleman, Paul J. ^{[1
]}

机构：

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

[2] Merck Res Labs, Dept Chem Modeling & Informat, West Point, PA 19486 USA

[3] Merck Res Labs, Dept In Vitro Sci, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Depress & Circadian Disorders, West Point, PA 19486 USA

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 14期

关键词：

PROTEIN-COUPLED RECEPTORS; REM-SLEEP; POTENT; NARCOLEPSY; HYPOCRETINS; DRUGS; RATS; DISORDERS; RAMELTEON; REDUCTION;

D O I：

10.1021/jm100541c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquina-zoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.

引用

页码：5320 / 5332

页数：13

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