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

Abstract

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 (OX1 R and OX2 R), 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 OX1 R or OX2 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.

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

“…This value was not significantly different from vehicle-treated animals, and well below the minimal amount of time typically required for narcoleptic canines to complete the FECT33. The MK-1064 dosage used in dogs in these experiments was exceedingly high; plasma concentrations reached 15.3 μM (C max ), which is 500-fold higher than the minimum needed for sleep-promoting efficacy (0.028 μM)29.…”

“…MK-1064 is a novel 2-SORA whose synthesis, discovery, and initial characterization has been recently described29. Here, we assessed the in vitro properties of MK-1064 and its sleep-promoting efficacy in preclinical species and human subjects to characterize its mechanism of action to evaluate the potential of OX 2 R antagonism as a therapeutic strategy for insomnia.…”

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

“…Merck has two DORAs which have reached clinical trials for the treatment of insomnia, Filorexant and MW molecular weight Suvorexant, and has reported developing a SORA (MK-1064) for insomnia as well [69]. Filorexant is a pyridl piperidine which has sleep promoting effects in rats, mice and dogs [70,71].…”

Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia

“…Similarly, a newly developed selective OX2R antagonist, compound 1m, has been reported to primarily increase NREM sleep time with minimal effects on REM sleep when administered in mice during the dark phase (Etori et al, 2014). Efficacy on both NREM and REM sleep has been shown with a number of selective OX2R antagonists from Merck: compound 18 (Mercer et al, 2013), MK-1064 (Roecker et al, 2014a), MK-3697 (Roecker et al, 2014b), compound PE-6 [(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((8-fluoroquinolin-4-yl)oxy)-2-methylpiperidin-1-yl)methanone] (Raheem et al, 2015), and 2-SORA 19 [(R)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(4-(5-chloro-2-methylpyrimidin-4-yl)-7-methyl-1,4-diazepan-1-yl)methanone] (Roecker et al, 2015) in rodent models. However, dose-response effects have not been reported with these compounds, and the single dose tested might have been high enough to promote both sleep states.…”