Cover image for Vol. 10 Issue 4

Editor-in-Chief: Natalia Ortúzar

Impact Factor: 3.046

ISI Journal Citation Reports © Ranking: 2013: 18/58 (Chemistry Medicinal); 75/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

February 10, 2012

VIP: Discovery of [(2R,5R)-5-{[(5-Fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): A Dual Orexin Receptor Antagonist with Potent Sleep-Promoting Properties

VIP: Discovery of [(2R,5R)-5-{[(5-Fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): A Dual Orexin Receptor Antagonist with Potent Sleep-Promoting PropertiesPaul J. Coleman,* John D. Schreier, Christopher D. Cox, Michael J. Breslin, David B. Whitman, Michael J. Bogusky, Georgia B. McGaughey, Rodney A. Bednar, Wei Lemaire, Scott M. Doran, Steven V. Fox, Susan L. Garson, Anthony L. Gotter, C. Meacham Harrell, Duane R. Reiss, Tamara D. Cabalu, Donghui Cui, Thomayant Prueksaritanont, Joanne Stevens, Pamela L. Tannenbaum, Richard G. Ball, Joyce Stellabott, Steven D. Young, George D. Hartman, Christopher J. Winrow, John J. Renger

Insomnia and related sleep disorders have significant consequences on health and well-being. A lack of sleep impairs next-day function, and the incidence of sleep disorders increases with age. Orexin-secreting neurons that project from the hypothalamus stimulate wakefulness. The function of these excitatory neuropeptides was discovered through genetic studies on narcoleptic dogs and transgenic mice, linking dysfunction of this system with excessive sleepiness. Orexin antagonists induce sleep by selectively blocking wake-promoting signals, and this concept has been shown to have utility in clinical studies with orexin antagonists.

In this article, Paul J. Coleman and colleagues at Merck Research Laboratories describe the design and synthesis of a potent dual orexin receptor antagonist (DORA) MK-6096. Analysis of the stereoelectronic properties of α-methyl piperidine carboxamides was used to design 2,5-disubstituted piperidine carboxamides with axially oriented substituents. MK-6096 is currently in phase II clinical studies.

Received January 13, 2012; published online February 3, 2012, DOI: 10.1002/cmdc.201200025.

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