Discovery of 5"-Chloro-N-[( 5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3"-terpyridine-3′-carboxamide (MK-1064): A Selective Orexin 2 Receptor Antagonist (2-SORA) for the Treatment of Insomnia

被引：60

作者：

Roecker, Anthony J. ^{[1
]}

Mercer, Swati P. ^{[1
]}

Schreier, John D. ^{[1
]}

Cox, Christopher D. ^{[1
]}

Fraley, Mark E. ^{[1
]}

Steen, Justin T. ^{[1
]}

Lemaire, Wei ^{[2
]}

Bruno, Joseph G. ^{[2
]}

Harrell, C. Meacham ^{[3
]}

Garson, Susan L. ^{[3
]}

Gotter, Anthony L. ^{[3
]}

Fox, Steven V. ^{[2
]}

Stevens, Joanne ^{[2
]}

Tannenbaum, Pamela L. ^{[2
]}

Prueksaritanont, Thomayant ^{[4
]}

Cabalu, Tamara D. ^{[4
]}

Cui, Donghui ^{[4
]}

Stellabott, Joyce ^{[5
]}

Hartman, George D. ^{[1
]}

Young, Steven D. ^{[1
]}

Winrow, Christopher J. ^{[3
]}

Renger, John J. ^{[3
]}

Coleman, Paul J. ^{[1
]}

机构：

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

[2] Merck, Dept In Vitro Pharmacol, West Point, PA USA

[3] Merck, Dept Neurosci, West Point, PA USA

[4] Merck, Dept Drug Metab, West Point, PA USA

[5] Merck, Dept Basic Pharmaceut Sci, West Point, PA USA

来源：

CHEMMEDCHEM | 2014年 / 9卷 / 02期

关键词：

antagonists; insomnia; medicinal chemistry; neurotransmitters; orexin receptors; PROTEIN-COUPLED RECEPTORS; PHARMACOLOGICAL CHARACTERIZATION; IN-VIVO; SLEEP; POTENT; ALMOREXANT; NARCOLEPSY; PROMOTION; ZOLPIDEM; NEURONS;

D O I：

10.1002/cmdc.201300447

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1R and OX2R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1R or OX 2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[( 5,6-dimethoxypyridin-2-yl) methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.

引用

页码：311 / 322

页数：12

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