Discovery of the Dual Orexin Receptor Antagonist [(7<i>R</i>)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2<i>H</i>-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia

Cox, Christopher D.; Breslin, Michael J.; Whitman, David B.; Schreier, John D.; McGaughey, Georgia B.; Bogusky, Michael J.; Roecker, Anthony J.; Mercer, Swati P.; Bednar, Rodney A.; Lemaire, Wei; Bruno, Joseph G.; Reiss, Duane R.; Harrell, C. Meacham; Murphy, Kathy; Garson, Susan L.; Doran, Scott M.; Prueksaritanont, Thomayant; Anderson, Wayne B.; Tang, Cuyue; Roller, Shane; Cabalu, Tamara D.; Cui, Donghui; Hartman, George D.; Young, Steven D.; Koblan, Ken S.; Winrow, Christopher J.; Renger, John J.; Coleman, Paul J.

doi:10.1021/jm100541c

Cited by 336 publications

(204 citation statements)

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“…Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4,5).…”

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confidence: 99%

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Irukayama-Tomobe

Ogawa

Tominaga

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexindeficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists. neuropeptides produced by neurons exclusively localized to the lateral hypothalamus that act on two G protein-coupled receptors termed OX1R and OX2R (1). Orexin-producing neurons send axons diffusely through the central nervous system, with especially dense innervations to several nuclei involved in sleep/wakefulness regulation (2, 3). Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4, 5).A crucial role of the orexin system in the regulation of sleep/ wakefulness was initially uncovered by the discovery that OX2R-deficient dogs (6) and prepro-orexin knockout (Hcrt −/− , abbreviated as OXKO) mice (2) exhibited symptoms resembling human narcolepsy-cataplexy. According to the clinical definition by the International Classification of Sleep Disorders-Third Edition, two types of narcoleptic disorders are categorized (7). Narcolepsy type 1 is characterized by the existence of cataplexy and low levels of orexin-A in cerebrospinal fluid (CSF) (8-10). However, patients with narcolepsy type 2 show no cataplexy and normal orexin-A levels in CSF. Narcolepsy-cataplexy, or narcolepsy type 1 (11), is characterized by a marked instability of sleep/ wake state transitions, resulting in nonrapid eye movement (NREM) sleep-related symptoms (e.g., excessive daytime sleepiness, "sleep attacks," and fragmented nighttime sleep), and rapid eye movement (REM) sleep-related symptoms (e.g., cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). In polysomnography, narcolepsy-cataplexy patients show markedly reduced daytime sleep latency, and sleep-onset REM periods (SOREMs). Currently available treatments for narcolepsyca...

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confidence: 99%

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Irukayama-Tomobe

Ogawa

Tominaga

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Some of those have been radio-labeled for in vivo imaging. Clinical trials have been performed for ligands at CRF1 receptors [39,[42][43][44][45][46][47], at orexin receptors [48,49], at the NPY receptors [50,51], the opioid receptors [52], melanocortin -4-receptors (MC4-R) [53][54][55], melanin concentrating hormone receptors (MCH1-R) [56] and growth hormone secretagogue receptor 1 (ghrelin; GHS1-R) [57,58].…”

Section: Hypothalamus As a Potential Target For Drug Development In Tmentioning

confidence: 99%

“…Almorexant (31) (ACT-078573), SB-649868 (32) and MK-4305 (33) (Figure 7) as well as Merck-DORA 1 and Merck-DORA-5 belong to the first group. Almorexant and SB-649868 improved the natural sleep architecture by increasing the time spent in REM and non-REM sleep phase in contrast to the GABA modulator zolpidem which reduces the time in these sleep stages [48,49]. Both were subjected to clinical trials (Almorexant to phase III and SB-649868 to phase I) but the latter was delayed in further testing by preclinical toxicological findings.…”

Section: Non-peptide Ox-r Ligandsmentioning

confidence: 99%

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Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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“…) is another compound with potent dual orexin receptor antagonistic activity (Cox et al, 2010). This compound is currently under Phase IIIb clinical trials for the treatment of primary insomnia.…”

Section: Mmandts 14mentioning

confidence: 99%

Overview of orexin/hypocretin system

Mieda

Sakurai

2012

Progress in Brain Research

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A series of recent studies has established the orexin/hypocretin system as a critical regulator of sleep/wake states. Its deficiency results in the sleep disorder narcolepsy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies and future perspectives.

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Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia

Cited by 336 publications

References 49 publications

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Overview of orexin/hypocretin system

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