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Orexin receptor antagonists: a review of promising compounds patented since 2006

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Pages 307-324 | Published online: 24 Feb 2010

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Abdelaziz Ghanemi & Xintian Hu. (2015) Targeting the orexinergic system: Mainly but not only for sleep-wakefulness therapies. Alexandria Journal of Medicine 51:4, pages 279-286.
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John A Christopher & Miles S Congreve. (2013) Treatment and prevention of various therapeutic conditions using OX receptor antagonistic activity (WO2012081692). Expert Opinion on Therapeutic Patents 23:2, pages 273-277.
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Octavian C Ioachimescu & Ali A El-Solh. (2012) Pharmacotherapy of insomnia. Expert Opinion on Pharmacotherapy 13:9, pages 1243-1260.
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Articles from other publishers (48)

Clemens Muehlan, Catherine Roch, Cedric Vaillant & Jasper Dingemanse. (2023) The orexin story and orexin receptor antagonists for the treatment of insomnia. Journal of Sleep Research 32:6.
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Shahram Zarrabian, Esmail Riahi, Sara Karimi, Yasaman Razavi & Abbas Haghparast. (2020) The potential role of the orexin reward system in future treatments for opioid drug abuse. Brain Research 1731, pages 146028.
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Mathieu RappasAmmar A. E. AliKirstie A. BennettJason D. BrownSarah J. BucknellMiles Congreve, Robert M. CookeGabriella CsekeChris de GraafAndrew S. DoréJames C. ErreyAli JazayeriFiona H. MarshallJonathan S. MasonRichard MouldJayesh C. PatelBenjamin G. TehanMalcolm WeirJohn A. Christopher. (2019) Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis. Journal of Medicinal Chemistry 63:4, pages 1528-1543.
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Jyrki P. Kukkonen. 2019. The Orexin/Hypocretin System. The Orexin/Hypocretin System 31 68 .
Jana Janockova, Rafael Dolezal, Eugenie Nepovimova, Tereza Kobrlova, Marketa Benkova, Kamil Kuca, Jan Konecny, Eva Mezeiova, Michaela Melikova, Vendula Hepnarova, Avi Ring, Ondrej Soukup & Jan Korabecny. (2018) Investigation of New Orexin 2 Receptor Modulators Using In Silico and In Vitro Methods. Molecules 23:11, pages 2926.
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Larry Yet. 2018. Privileged Structures in Drug Discovery. Privileged Structures in Drug Discovery 194 236 .
Ainoleena Turku, Maiju K. Rinne, Gustav Boije af Gennäs, Henri Xhaard, Dan Lindholm & Jyrki P. Kukkonen. (2017) Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity. PLOS ONE 12:6, pages e0178526.
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Rita Machaalani, Nicholas J. Hunt & Karen A. Waters. 2016. Neuropathology of Drug Addictions and Substance Misuse. Neuropathology of Drug Addictions and Substance Misuse 133 145 .
Ruben Vardanyan & Victor Hruby. 2016. Synthesis of Best-Seller Drugs. Synthesis of Best-Seller Drugs 65 76 .
Dirk Behnke, Simona Cotesta, Samuel Hintermann, Markus Fendt, Christine E. Gee, Laura H. Jacobson, Grit Laue, Arndt Meyer, Trixie Wagner, Sangamesh Badiger, Vinod Chaudhari, Murali Chebrolu, Chetan Pandit, Daniel Hoyer & Claudia Betschart. (2015) Discovery of 1 H -pyrazolo[3,4- b ]pyridines as potent dual orexin receptor antagonists (DORAs). Bioorganic & Medicinal Chemistry Letters 25:23, pages 5555-5560.
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John A. ChristopherSarah J. AvesJason BrownJames C. ErreySuki S. KlairChristopher J. Langmead, Oliver J. MaceRichard MouldJayesh C. PatelBenjamin G. TehanAndrei ZhukovFiona H. MarshallMiles Congreve. (2015) Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties. MedChemComm 6:5, pages 947-955.
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Michael Wilkinson & Richard E. Brown. 2015. An Introduction to Neuroendocrinology. An Introduction to Neuroendocrinology 257 285 .
Yu Yoshida, Taro Terauchi, Yoshimitsu Naoe, Yuji Kazuta, Fumihiro Ozaki, Carsten T. Beuckmann, Makoto Nakagawa, Michiyuki Suzuki, Ikuo Kushida, Osamu Takenaka, Takashi Ueno & Masahiro Yonaga. (2014) Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists. Bioorganic & Medicinal Chemistry 22:21, pages 6071-6088.
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Matthias Hoch, Helene van Gorsel, Joop van Gerven & Jasper Dingemanse. (2014) Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant. The Journal of Clinical Pharmacology 54:9, pages 979-986.
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R.J. Cady, J.E. Denson, L.Q. Sullivan & P.L. Durham. (2014) Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization. Neuroscience 269, pages 79-92.
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Thierry Sifferlen, Amandine Boller, Audrey Chardonneau, Emmanuelle Cottreel, Johannes Hoecker, Hamed Aissaoui, Jodi T. Williams, Christine Brotschi, Bibia Heidmann, Romain Siegrist, John Gatfield, Alexander Treiber, Catherine Brisbare-Roch, Francois Jenck & Christoph Boss. (2014) Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure–activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1. Bioorganic & Medicinal Chemistry Letters 24:4, pages 1201-1208.
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Anthony J. Roecker, Swati P. Mercer, John D. Schreier, Christopher D. Cox, Mark E. Fraley, Justin T. Steen, Wei Lemaire, Joseph G. Bruno, C. Meacham Harrell, Susan L. Garson, Anthony L. Gotter, Steven V. Fox, Joanne Stevens, Pamela L. Tannenbaum, Thomayant Prueksaritanont, Tamara D. Cabalu, Donghui Cui, Joyce Stellabott, George D. Hartman, Steven D. Young, Christopher J. Winrow, John J. Renger & Paul J. Coleman. (2014) 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 . ChemMedChem 9:2, pages 311-322.
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C J Winrow & J J Renger. (2014) Discovery and development of orexin receptor antagonists as therapeutics for insomnia. British Journal of Pharmacology 171:2, pages 283-293.
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Robert M. SearsAnn E. FinkMattis B. WigestrandClaudia R. FarbLuis de Lecea & Joseph E. LeDoux. (2013) Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proceedings of the National Academy of Sciences 110:50, pages 20260-20265.
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Ian B Hickie, Sharon L Naismith, Rébecca Robillard, Elizabeth M Scott & Daniel F Hermens. (2013) Manipulating the sleep-wake cycle and circadian rhythms to improve clinical management of major depression. BMC Medicine 11:1.
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Swati P. Mercer, Anthony J. Roecker, Susan Garson, Duane R. Reiss, C. Meacham Harrell, Kathy L. Murphy, Joseph G. Bruno, Rodney A. Bednar, Wei Lemaire, Donghui Cui, Tamara D. Cabalu, Cuyue Tang, Thomayant Prueksaritanont, George D. Hartman, Steven D. Young, Christopher J. Winrow, John J. Renger & Paul J. Coleman. (2013) Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs). Bioorganic & Medicinal Chemistry Letters 23:24, pages 6620-6624.
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Norihito Oi, Michiyuki SuzukiTaro TerauchiMasaki TokunagaYosuke Nakatani, Noboru YamamotoToshimitsu FukumuraMing-Rong ZhangTetsuya Suhara & Makoto Higuchi. (2013) Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor. Journal of Medicinal Chemistry 56:16, pages 6371-6385.
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Rita Machaalani, Nicholas J. Hunt & Karen A. Waters. (2013) Effects of changes in energy homeostasis and exposure of noxious insults on the expression of orexin (hypocretin) and its receptors in the brain. Brain Research 1526, pages 102-122.
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Thierry Sifferlen, Ralf Koberstein, Emmanuelle Cottreel, Amandine Boller, Thomas Weller, John Gatfield, Catherine Brisbare-Roch, Francois Jenck & Christoph Boss. (2013) Structure–activity relationship studies and sleep-promoting activity of novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 2. Bioorganic & Medicinal Chemistry Letters 23:13, pages 3857-3863.
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Jasper Dingemanse & Petra Hoever. (2013) Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects. Drugs in R&D 13:2, pages 145-151.
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Klaus Heese. (2013) G Proteins, p60TRP, and Neurodegenerative Diseases. Molecular Neurobiology 47:3, pages 1103-1111.
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Thierry Sifferlen, Ralf Koberstein, Emmanuelle Cottreel, Amandine Boller, Thomas Weller, John Gatfield, Catherine Brisbare-Roch, Francois Jenck & Christoph Boss. (2013) Synthesis, structure–activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1. Bioorganic & Medicinal Chemistry Letters 23:7, pages 2212-2216.
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Olivier CivelliRainer K. Reinscheid, Yan ZhangZhiwei WangRobert FredrikssonHelgi B. Schiöth. (2013) G Protein–Coupled Receptor Deorphanizations. Annual Review of Pharmacology and Toxicology 53:1, pages 127-146.
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Jyrki P. Kukkonen. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. American Journal of Physiology-Cell Physiology 304:1, pages C2-C32.
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Christopher J. Winrow, Anthony L. Gotter, Paul J. Coleman, Richard Hargreaves & John J. Renger. 2012. Drug Discovery for Psychiatric Disorders. Drug Discovery for Psychiatric Disorders 416 442 .
Ian K. Mangion, Benjamin D. Sherry, Jingjun Yin & Fred J. Fleitz. (2012) Enantioselective Synthesis of a Dual Orexin Receptor Antagonist. Organic Letters 14:13, pages 3458-3461.
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John A Christopher. (2012) Orexin receptor antagonists. Pharmaceutical Patent Analyst 1:3, pages 329-346.
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Anthony L. Gotter, Andrea L. Webber, Paul J. Coleman, John J. Renger & Christopher J. Winrow. (2012) International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology. Pharmacological Reviews 64:3, pages 389-420.
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Chad Ruoff & Christian Guilleminault. (2012) Hypocretin receptor antagonists for insomnia: rationale and clinical data. Clinical Investigation 2:6, pages 623-637.
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Rong Jiang, Xinyi Song, Purva Bali, Anthony Smith, Claudia Ruiz Bayona, Li Lin, Michael D. Cameron, Patricia H. McDonald, Paul J. Kenny & Theodore M. Kamenecka. (2012) Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists. Bioorganic & Medicinal Chemistry Letters 22:12, pages 3890-3894.
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Paul 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. (2012) Discovery of [(2 R ,5 R )-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 . ChemMedChem 7:3, pages 415-424.
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Marc Laburthe & Thierry Voisin. (2012) The orexin receptor OX 1 R in colon cancer: a promising therapeutic target and a new paradigm in G protein-coupled receptor signalling through ITIMs . British Journal of Pharmacology 165:6, pages 1678-1687.
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Yu Zhang, Shengjie Fan, Na Hu, Ming Gu, Chunxiao Chu, Yiming Li, Xiong Lu & Cheng Huang. (2012) Rhein Reduces Fat Weight in db/db Mouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPAR γ Signaling . PPAR Research 2012, pages 1-9.
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Anthony L. Gotter, Anthony J. Roecker, Richard Hargreaves, Paul J. Coleman, Christopher J. Winrow & John J. Renger. 2012. Orexin/Hypocretin System. Orexin/Hypocretin System 163 188 .
Tatsuhiko Fujimoto, Yoshihide Tomata, Jun Kunitomo, Mariko Hirozane & Shogo Marui. (2011) Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 21:21, pages 6409-6413.
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Tatsuhiko Fujimoto, Jun Kunitomo, Yoshihide Tomata, Keiji Nishiyama, Masato Nakashima, Mariko Hirozane, Shin-ichi Yoshikubo, Keisuke Hirai & Shogo Marui. (2011) Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 21:21, pages 6414-6416.
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Richard J Ward, John D Pediani & Graeme Milligan. (2011) Ligand-induced internalization of the orexin OX1 and cannabinoid CB1 receptors assessed via N-terminal SNAP and CLIP-tagging. British Journal of Pharmacology 162:6, pages 1439-1452.
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Thomas E. ScammellChristopher J. Winrow. (2011) Orexin Receptors: Pharmacology and Therapeutic Opportunities. Annual Review of Pharmacology and Toxicology 51:1, pages 243-266.
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Alessandro Gozzi, Giuliano Turrini, Laura Piccoli, Mario Massagrande, David Amantini, Marinella Antolini, Prisca Martinelli, Nicola Cesari, Dino Montanari, Michela Tessari, Mauro Corsi & Angelo Bifone. (2011) Functional Magnetic Resonance Imaging Reveals Different Neural Substrates for the Effects of Orexin-1 and Orexin-2 Receptor Antagonists. PLoS ONE 6:1, pages e16406.
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Fayi Yao & Robert George MacKenzie. (2010) Obesity Drug Update: The Lost Decade?. Pharmaceuticals 3:12, pages 3494-3521.
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Fabrizio Micheli, Marinella Antolini, Romano Di Fabio, Annalisa Pellacani & Alfonso Pozzan. (2010) 2-Methyl-3-furanyl-4H-1,2,4-triazol-3-ylthioamides: A new class of selective orexin 2 antagonists. Bioorganic & Medicinal Chemistry Letters 20:22, pages 6405-6407.
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John Gatfield, Catherine Brisbare-Roch, Francois Jenck & Christoph Boss. (2010) Orexin Receptor Antagonists: A New Concept In CNS Disorders?. ChemMedChem 5:8, pages 1197-1214.
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Christopher D. Cox, Michael J. Breslin, David B. Whitman, John D. Schreier, Georgia B. McGaughey, Michael J. Bogusky, Anthony J. Roecker, Swati P. Mercer, Rodney A. Bednar, Wei Lemaire, Joseph G. Bruno, Duane R. Reiss, C. Meacham Harrell, Kathy L. Murphy, Susan L. Garson, Scott M. Doran, Thomayant Prueksaritanont, Wayne B. Anderson, Cuyue Tang, Shane Roller, Tamara D. Cabalu, Donghui Cui, George D. Hartman, Steven D. Young, Ken S. Koblan, Christopher J. Winrow, John J. Renger & Paul J. Coleman. (2010) Discovery of the Dual Orexin Receptor Antagonist [(7 R )-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2 H -1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia . Journal of Medicinal Chemistry 53:14, pages 5320-5332.
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