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

作者：Coleman Paul J^*; Schreier John D; Cox Christopher D; Breslin Michael J; Whitman David B; Bogusky Michael J; McGaughey Georgia B; Bednar Rodney A; Lemaire Wei; Doran Scott M; Fox Steven V; Garson Susan L; Gotter Anthony L; Harrell C Meacham; Reiss Duane R; Cabalu Tamara D; Cui Donghui; Prueksaritanont Thomayant; Stevens Joanne; Tannenbaum Pamela L; Ball Richard G; Stellabott Joyce; Young Steven D; Hartman George D; Winrow Christopher J; Renger John J

来源：ChemMedChem, 2012, 7(3): 415-424.

DOI：10.1002/cmdc.201200025

• insomnia
• medicinal chemistry
• neurotransmitters
• orexins
• receptors

Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of a-methylpiperidine carboxamide dual orexin 1 and orexin 2 receptor (OX1R/OX2R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.

• 出版日期2012-3-5