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The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia

Coleman, Paul J., Gotter, Anthony L., Herring, W. Joseph, Winrow, Christopher J., Renger, John J.·2017·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-010716-104837

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Abstract

Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA A ) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABA A receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage–specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.

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Hoever, P., Dorffner, G., Beneš, H., Penzel, T., Danker‐Hopfe, H., Barbanoj, M. J., Pillar, G., Saletu, B., Polo, O. J., Kunz, D., et al. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.370 · Cited by 125
Orexin / hypocretin 1 receptor antagonist reduces heroin self‐administration and cue‐induced heroin seeking
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Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone
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Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis
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Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression
Nollet, M., Gaillard, P., Minier, F., Tanti, A., Belzung, C., & Leman, S. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.04.022 · Cited by 120
I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation
Ito, N., Yabe, T., Gamo, Y., Nagai, T., Oikawa, T., Yamada, H., & Hanawa, T. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.09.042 · Cited by 117
Clinical management of sleep disturbances in Alzheimer's disease: current and emerging strategies
Urrestarazu, E., & Iriarte, J. (2016) · Nature and Science of Sleep · doi:10.2147/nss.s76706 · Cited by 117
Parkinsonism with excessive daytime sleepiness
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Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder
Strawn, J. R., Pyne‐Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L., Baker, D. G., & Geracioti, T. D. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.01.001 · Cited by 109
Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons
Eriksson, K. S., Sergeeva, O. A., Selbach, O., & Haas, H. L. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03243.x · Cited by 107
The Dual Orexin Receptor Antagonist Almorexant Induces Sleep and Decreases Orexin-Induced Locomotion by Blocking Orexin 2 Receptors
Mang, G. M., Dürst, T., Bürki, H., Imobersteg, S., Abramowski, D., Schuepbach, E., Hoyer, D., Fendt, M., & Gee, C. E. (2012) · SLEEP · doi:10.5665/sleep.2232 · Cited by 105
Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia
Johnson, P. L., Samuels, B. C., Fitz, S. D., Lightman, S. L., Lowry, C. A., & Shekhar, A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.38 · Cited by 101
The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
Gotter, A. L., Winrow, C. J., Brunner, J., Garson, S. L., Fox, S. V., Binns, J., Harrell, C. M., Cui, D., Yee, K. L., Stiteler, M., et al. (2013) · BMC Neuroscience · doi:10.1186/1471-2202-14-90 · Cited by 101
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A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects
Bonaventure, P., Yun, S., Johnson, P. L., Shekhar, A., Fitz, S. D., Shireman, B. T., Lebold, T. P., Nepomuceno, D. H., Lord, B., Wennerholm, M. L., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.220392 · Cited by 101
Orexins and their receptors from fish to mammals: A comparative approach
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Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition
Uslaner, J. M., Tye, S. J., Eddins, D. M., Wang, X., Fox, S. V., Savitz, A. T., Binns, J., Cannon, C. E., Garson, S. L., Yao, L., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005213 · Cited by 91
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Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist
Yoshida, Y., Naoe, Y., Terauchi, T., Ozaki, F., Doko, T., Takemura, A., Tanaka, T., Sorimachi, K., Beuckmann, C. T., Suzuki, M., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00217 · Cited by 90
Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia
Bonaventure, P., Shelton, J. E., Yun, S., Nepomuceno, D. H., Sutton, S. W., Aluisio, L. E., Fraser, I. C., Lord, B., Shoblock, J. R., Welty, N., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.225466 · Cited by 87
Orexin and psychiatric symptoms in suicide attempters
Brundin, L., Petersén, Å., Björkqvist, M., & Träskman‐Bendz, L. (2006) · Journal of Affective Disorders · doi:10.1016/j.jad.2006.10.019 · Cited by 87
The Hypocretin/Orexin System: An Increasingly Important Role in Neuropsychiatry
Chen, Q., de Lecea, L., Hu, Z., & Gao, D. (2014) · Medicinal Research Reviews · doi:10.1002/med.21326 · Cited by 86
Microinjection of orexin into the rat nucleus tractus solitarius causes increases in blood pressure
Smith, P., Connolly, B. C., & Ferguson, A. V. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03048-2 · Cited by 85
Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man
Gotter, A. L., Forman, M. S., Harrell, C. M., Stevens, J., Svetnik, V., Yee, K. L., Li, X., Roecker, A. J., Fox, S. V., Tannenbaum, P. L., et al. (2016) · Scientific Reports · doi:10.1038/srep27147 · Cited by 84
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Orexin signaling in recombinant neuron‐like cells
Holmqvist, T., Åkerman, K. E. O., & Kukkonen, J. P. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03101-0 · Cited by 80
Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats
Schmeichel, B. E., Barbier, E., Misra, K. K., Contet, C., Schlosburg, J. E., Grigoriadis, D., Williams, J. P., Karlsson, C., Pitcairn, C., Heilig, M., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.293 · Cited by 79
Effects of suvorexant on sleep architecture and power spectral profile in patients with insomnia: analysis of pooled phase 3 data
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Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats
Whitman, D. B., Cox, C. D., Breslin, M. J., Brashear, K. M., Schreier, J. D., Bogusky, M. J., Bednar, R. A., Lemaire, W., Bruno, J. G., Hartman, G. D., et al. (2009) · ChemMedChem · doi:10.1002/cmdc.200900069 · Cited by 74
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Point mutations of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid(A) receptor affecting modulation of the channel by ligands of the benzodiazepine binding site.
Buhr, A., Baur, R., Malherbe, P., & Sigel, E. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)08998-9 · Cited by 73
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
Roecker, A. J., Mercer, S. P., Schreier, J. D., Cox, C. D., Fraley, M. E., Steen, J. T., Lemaire, W., Bruno, J. G., Harrell, C. M., Garson, S. L., et al. (2013) · ChemMedChem · doi:10.1002/cmdc.201300447 · Cited by 70
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Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt
Brundin, L., Björkqvist, M., Träskman‐Bendz, L., & Petersén, Å. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.04.011 · Cited by 65
Binding kinetics differentiates functional antagonism of orexin‐2 receptor ligands
Mould, R. F., Brown, J. D., Marshall, F. H., & Langmead, C. J. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12245 · Cited by 63
OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO 2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES
Johnson, P. L., Federici, L. M., Fitz, S. D., Renger, J. J., Shireman, B. T., Winrow, C. J., Bonaventure, P., & Shekhar, A. (2015) · Depression and Anxiety · doi:10.1002/da.22403 · Cited by 63
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Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization
Cady, R. J., Denson, J. E., Sullivan, L., & Durham, P. L. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.03.043 · Cited by 61
Orexin receptors couple to Ca2+ channels different from store-operated Ca2+ channels
Kukkonen, J. P., & �kerman, K. E. O. (2001) · Neuroreport · doi:10.1097/00001756-200107030-00046 · Cited by 61
Almorexant Promotes Sleep and Exacerbates Cataplexy in a Murine Model of Narcolepsy
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The relationship between sleep and cognition in Parkinson's disease: A meta-analysis
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Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease
Asai, H., Hirano, M., Furiya, Y., Udaka, F., Morikawa, M., Kanbayashi, T., Shimizu, T., & Ueno, S. (2008) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2008.11.007 · Cited by 57
Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant
Dietrich, H., & Jenck, F. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1933-5 · Cited by 56
Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders
Fabio, R. D., Pellacani, A., Faedo, S., Roth, A. L., Piccoli, L., Gerrard, P. A., Porter, R. A., Johnson, C. N., Thewlis, K. M., Donati, D., et al. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.06.086 · Cited by 53
Neuroendocrine Proopiomelanocortin Neurons Are Excited by Hypocretin/Orexin
Acuna, C., & van den Pol, A. N. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5147-08.2009 · Cited by 52
Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys
Tannenbaum, P. L., Tye, S. J., Stevens, J., Gotter, A. L., Fox, S. V., Savitz, A. T., Coleman, P. J., Uslaner, J. M., Kuduk, S. D., Hargreaves, R. J., et al. (2016) · SLEEP · doi:10.5665/sleep.5536 · Cited by 51
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Knockdown of orexin type 1 receptor in rat locus coeruleus increases REM sleep during the dark period
Chen, L., McKenna, J. T., Bolortuya, Y., Winston, S. H., Thakkar, M. M., Basheer, R., Brown, R. E., & McCarley, R. W. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07401.x · Cited by 49
Involvement of TRPC3 channels in calcium oscillations mediated by OX1 orexin receptors
Peltonen, H. M., Magga, J. M., Bart, G., Turunen, P. M., Antikainen, M. S. H., Kukkonen, J. P., & Åkerman, K. E. O. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.05.077 · Cited by 49
Differential sleep-promoting effects of dual orexin receptor antagonists and GABAAreceptor modulators
Gotter, A. L., Garson, S. L., Stevens, J., Munden, R. L., Fox, S. V., Tannenbaum, P. L., Yao, L., Kuduk, S. D., McDonald, T., Uslaner, J. M., et al. (2014) · BMC Neuroscience · doi:10.1186/1471-2202-15-109 · Cited by 49
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Differential Effects of the Dual Orexin Receptor Antagonist Almorexant and the GABAA-α1 Receptor Modulator Zolpidem, Alone or Combined with Ethanol, on Motor Performance in the Rat
Steiner, M. A., Lecourt, H., Strasser, D. S., Roch, C., & Jenck, F. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.224 · Cited by 48
Electroencephalographic Power Spectral Density Profile of the Orexin Receptor Antagonist Suvorexant in Patients with Primary Insomnia and Healthy Subjects
Ma, J., Svetnik, V., Snyder, E., Lines, C., Roth, T. G., & Herring, W. J. (2014) · SLEEP · doi:10.5665/sleep.4068 · Cited by 48
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Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography
Abadie, P., Rioux, P. P., Scatton, B., Zarifian, E., Barré, L., Patat, A. A., & Baron, J. (1996) · European Journal of Pharmacology · doi:10.1016/0014-2999(95)00633-8 · Cited by 46
Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate
Letavic, M. A., Bonaventure, P., Carruthers, N. I., Dugovic, C., Koudriakova, T. B., Lord, B., Lovenberg, T. W., Ly, K. S., Mani, N. S., Nepomuceno, D. H., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00742 · Cited by 45
Discovery of Dual Orexin Receptor Antagonists (DORAs) for the Treatment of Insomnia
Coleman, P. J., Cox, C. D., & Roecker, A. J. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026611109060696 · Cited by 44
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Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent, Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist
Boss, C., Roch, C., Steiner, M. A., Treiber, A., Dietrich, H., Jenck, F., von Raumer, M., Sifferlen, T., Brotschi, C., Heidmann, B., et al. (2014) · ChemMedChem · doi:10.1002/cmdc.201402258 · Cited by 42
Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
Callander, G. E., Olorunda, M., Monna, D., Schuepbach, E., Langenegger, D., Betschart, C., Hintermann, S., Behnke, D., Cotesta, S., Fendt, M., et al. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00230 · Cited by 41
Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators
Ramirez, A. D., Gotter, A. L., Fox, S. V., Tannenbaum, P. L., Yao, L., Tye, S. J., McDonald, T. P., Brunner, J., Garson, S. L., Reiss, D. R., et al. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00254 · Cited by 40
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Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs
Tannenbaum, P. L., Stevens, J., Binns, J., Savitz, A. T., Garson, S. L., Fox, S. V., Coleman, P. J., Kuduk, S. D., Gotter, A. L., Marino, M. J., et al. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00182 · Cited by 39
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Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats
Fox, S. V., Gotter, A. L., Tye, S. J., Garson, S. L., Savitz, A. T., Uslaner, J. M., Brunner, J. I., Tannenbaum, P. L., McDonald, T. P., Hodgson, R. A., et al. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.139 · Cited by 38
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The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats
Morairty, S. R., Wilk, A. J., Lincoln, W. U., Neylan, T. C., & Kilduff, T. S. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00003 · Cited by 38
Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat
Beig, M. I., Dampney, B. W., & Carrive, P. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.09.012 · Cited by 32
Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons
Kalogiannis, M., Grupke, S. L., Potter, P. E., Edwards, J. G., Chemelli, R. M., Kisanuki, Y. Y., Yanagisawa, M., & Leonard, C. S. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07259.x · Cited by 30
Discovery of MK-3697: A selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia
Roecker, A. J., Reger, T. S., Mattern, C., Mercer, S. P., Bergman, J. M., Schreier, J. D., Cube, R. V., Cox, C. D., Li, D., Lemaire, W., et al. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.08.041 · Cited by 30
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Cardiovascular Actions of Orexin‐A in the Rat Subfornical Organ
Smith, P., Samson, W. K., & Ferguson, A. V. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01497.x · Cited by 29
Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists
Fujimoto, T., Kunitomo, J., Tomata, Y., Nishiyama, K., Nakashima, M., Hirozane, M., Yoshikubo, S.-I., Hirai, K., & Marui, S. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.08.093 · Cited by 28
Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen
Liebig, J. (1832) · Annalen der Pharmacie · doi:10.1002/jlac.18320010203 · Cited by 28
Discovery and in vitro and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide as a novel class of dual orexin receptor antagonist
Suzuki, R., Nozawa, D., Futamura, A., Nishikawa‐Shimono, R., Abe, M., Hattori, N., Ohta, H., Araki, Y., Kambe, D., Ohmichi, M., et al. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.01.044 · Cited by 25
Orexin/Hypocretin: Wired for Wakefulness
Mochizuki, T., & Scammell, T. E. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00474-3 · Cited by 24
Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties
Kuduk, S. D., Skudlarek, J. W., Marco, C. N. D., Bruno, J. G., Pausch, M. H., O’Brien, J. A., Cabalu, T. D., Stevens, J., Brunner, J., Tannenbaum, P. L., et al. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.04.066 · Cited by 21
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Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists
Faedo, S., Perdonà, E., Antolini, M., Fabio, R. D., Pich, E. M., & Corsi, M. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.07.007 · Cited by 19
Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties
Christopher, J. A., Aves, S. J., Brown, J. D., Errey, J. C., Klair, S., Langmead, C. J., Mace, O. J., Mould, R. F., Patel, J. C., Tehan, B. G., et al. (2015) · MedChemComm · doi:10.1039/c5md00027k · Cited by 18
The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems
Parks, G. S., Warrier, D. R., Dittrich, L., Schwartz, M. D., Palmerston, J. B., Neylan, T. C., Morairty, S. R., & Kilduff, T. S. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.256 · Cited by 17
Sleep Evaluation by Actigraphy for Patients With Alzheimer Disease—Reply
Ju, Y. S., & Holtzman, D. M. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.3490 · Cited by 12
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Kisanuki YY, 2001, Sleep, 24, A22
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See all 131

Authors: Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
Department of Clinical Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
ORCID: Coleman, Paul J.
Gotter, Anthony L.
Herring, W. Joseph
Winrow, Christopher J.
Renger, John J.
Venue: Annual Review of Pharmacology and Toxicology
Publisher: Annual Reviews
Published: 2017-01-06
Volume: 57
Issue: 1
Pages: 509-533
ISSN: 0362-1642 (ISSN-L)
1545-4304
DOI: 10.1146/annurev-pharmtox-010716-104837
OpenAlex: W2492327128
Cited by: 128
References: 143
Citations by year: 2026: 5 · 2025: 11 · 2024: 18 · 2023: 9 · 2022: 20 · 2021: 13 · 2020: 13 · 2019: 21 · 2018: 9 · 2017: 8
FWCI: 1.33
Type: journal article
Language: en
Open access: closed
Locations: The Annual Review of Pharmacology and Toxicology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords: suvorexant, orexin receptor antagonists, insomnia, dual orexin receptor antagonists, orexin signaling, narcolepsy, GABA-A receptor agonists, sleep onset, REM sleep, pharmacokinetics, cognitive performance, wakefulness
MeSH terms: Sleep Aids, Pharmaceutical, Orexin Receptor Antagonists, Animals, Azepines, Humans, Sleep Initiation and Maintenance Disorders, Triazoles, Protein Structure, Secondary, Drug Discovery, Orexin Receptors

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The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia

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