Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements

被引：10

作者：

Roecker, Anthony J. ^{[1
]}

Mercer, Swati P. ^{[1
]}

Bergman, Jeffrey M. ^{[1
]}

Gilbert, Kevin F. ^{[1
]}

Kuduk, Scott D. ^{[1
]}

Harrell, C. Meacham ^{[2
]}

Garson, Susan L. ^{[2
]}

Fox, Steven V. ^{[2
]}

Gotter, Anthony L. ^{[2
]}

Tannenbaum, Pamela L. ^{[2
]}

Prueksaritanont, Thomayant ^{[3
]}

Cabalu, Tamara D. ^{[3
]}

Cui, Donghui ^{[3
]}

Lemaire, Wei ^{[4
]}

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, Dept In Vitro Pharmacol, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 21期

关键词：

Orexin; Antagonists; Sleep; Isostere; Quinazoline; OREXIN RECEPTOR ANTAGONISTS; P-GLYCOPROTEIN; SLEEP; POTENT; PROMOTION; INSOMNIA;

D O I：

10.1016/j.bmcl.2014.12.081

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4992 / 4999

页数：8

共 2 条

[1] Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)
Mercer, Swati P.
Roecker, Anthony J.
Garson, Susan
Reiss, Duane R.
Harrell, C. Meacham
Murphy, Kathy L.
Bruno, Joseph G.
Bednar, Rodney A.
Lemaire, Wei
Cui, Donghui
Cabalu, Tamara D.
Tang, Cuyue
Prueksaritanont, Thomayant
Hartman, George D.
Young, Steven D.
Winrow, Christopher J.
Renger, John J.
Coleman, Paul J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (24) : 6620 - 6624
[2] RENIN INHIBITORS CONTAINING ISOSTERIC REPLACEMENTS OF THE AMIDE BOND CONNECTING THE P3 AND P2 SITES
KALTENBRONN, JS
HUDSPETH, JP
LUNNEY, EA
MICHNIEWICZ, BM
NICOLAIDES, ED
REPINE, JT
ROARK, WH
STIER, MA
TINNEY, FJ
WOO, PKW
ESSENBURG, AD
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (02) : 838 - 845

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