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Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists

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† International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
‡ Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
§ School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
∥ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8584, United States
*Phone: +81-29-853-6437. E-mail: [email protected]
Cite this: J. Med. Chem. 2015, 58, 20, 7931–7937
Publication Date (Web):August 12, 2015
https://doi.org/10.1021/acs.jmedchem.5b00988
Copyright © 2015 American Chemical Society
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Abstract

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Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 μM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4′-methoxy-N,N-dimethyl-3′-[N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl)sulfamoyl]-(1,1′-biphenyl)-3-carboxamide 26.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b00988.

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This article is cited by 57 publications.

  1. Lasse Karhu, Aniket Magarkar, Alex Bunker, Henri Xhaard. Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study. The Journal of Physical Chemistry B 2019, 123 (12) , 2609-2622. https://doi.org/10.1021/acs.jpcb.8b10220
  2. Hiroshi Nagase, Naoshi Yamamoto, Masahiro Yata, Sayaka Ohrui, Takahiro Okada, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Yasuhiro Ogawa, Shigeto Hirayama, Daisuke Kuroda, Yurie Watanabe, Hiroaki Gouda, and Masashi Yanagisawa . Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies. Journal of Medicinal Chemistry 2017, 60 (3) , 1018-1040. https://doi.org/10.1021/acs.jmedchem.6b01418
  3. Ainoleena Turku, Alexandre Borrel, Teppo O. Leino, Lasse Karhu, Jyrki P. Kukkonen, and Henri Xhaard . Pharmacophore Model To Discover OX1 and OX2 Orexin Receptor Ligands. Journal of Medicinal Chemistry 2016, 59 (18) , 8263-8275. https://doi.org/10.1021/acs.jmedchem.6b00333
  4. Anthony J. Roecker, Christopher D. Cox, and Paul J. Coleman . Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia. Journal of Medicinal Chemistry 2016, 59 (2) , 504-530. https://doi.org/10.1021/acs.jmedchem.5b00832
  5. Alexander Heifetz, Mike J. Bodkin, and Philip C. Biggin . Discovery of the First Selective, Nonpeptidic Orexin 2 Receptor Agonists. Journal of Medicinal Chemistry 2015, 58 (20) , 7928-7930. https://doi.org/10.1021/acs.jmedchem.5b01394
  6. Chuan Hong, Noel J. Byrne, Beata Zamlynny, Srivanya Tummala, Li Xiao, Jennifer M. Shipman, Andrea T. Partridge, Christina Minnick, Michael J. Breslin, Michael T. Rudd, Shawn J. Stachel, Vanessa L. Rada, Jeffrey C. Kern, Kira A. Armacost, Scott A. Hollingsworth, Julie A. O’Brien, Dawn L. Hall, Terrence P. McDonald, Corey Strickland, Alexei Brooun, Stephen M. Soisson, Kaspar Hollenstein. Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Nature Communications 2021, 12 (1) https://doi.org/10.1038/s41467-021-21087-6
  7. Hiroshi Nagase. Encounter Leading to Success. Journal of Synthetic Organic Chemistry, Japan 2021, 79 (2) , 162-165. https://doi.org/10.5059/yukigoseikyokaishi.79.162
  8. Christoph Boss, John Gatfield, Christine Brotschi, Bibia Heidmann, Thierry Sifferlen, Markus Raumer, Gunther Schmidt, Jodi T. Williams, Alexander Treiber, Catherine Roch. The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders. ChemMedChem 2020, 15 (23) , 2286-2305. https://doi.org/10.1002/cmdc.202000453
  9. Erica Seigneur, Luis de Lecea. Hypocretin (Orexin) Replacement Therapies. Medicine in Drug Discovery 2020, 8 , 100070. https://doi.org/10.1016/j.medidd.2020.100070
  10. Eva Mezeiova, Jana Janockova, Jan Konecny, Tereza Kobrlova, Marketa Benkova, Rafael Dolezal, Lukas Prchal, Jana Karasova-Zdarova, Ondrej Soukup, Jan Korabecny. From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia. Bioorganic Chemistry 2020, 103 , 104179. https://doi.org/10.1016/j.bioorg.2020.104179
  11. Shinichi Takenoshita, Seiji Nishino. Pharmacologic Management of Excessive Daytime Sleepiness. Sleep Medicine Clinics 2020, 15 (2) , 177-194. https://doi.org/10.1016/j.jsmc.2020.02.006
  12. Coleman B. Calva, Jim R. Fadel. Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction. Brain Research 2020, 1731 , 145921. https://doi.org/10.1016/j.brainres.2018.08.024
  13. Huiling Tang, Qiumei Zhu, Wei Li, Siru Qin, Yinan Gong, Hong Wang, Seiji Shioda, Shanshan Li, Jin Huang, Baohu Liu, Yuxin Fang, Yangyang Liu, Shenjun Wang, Yongming Guo, Qing Xia, Yi Guo, Zhifang Xu. Neurophysiology and Treatment of Disorders of Consciousness Induced by Traumatic Brain Injury: Orexin Signaling as a Potential Therapeutic Target. Current Pharmaceutical Design 2019, 25 (39) , 4208-4220. https://doi.org/10.2174/1381612825666191029101830
  14. Hiroshi Yukitake, Tatsuhiko Fujimoto, Takashi Ishikawa, Atsushi Suzuki, Yuji Shimizu, Kentaro Rikimaru, Mitsuhiro Ito, Motohisa Suzuki, Haruhide Kimura. TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice. Pharmacology Biochemistry and Behavior 2019, 187 , 172794. https://doi.org/10.1016/j.pbb.2019.172794
  15. Miyo Kakizaki, Yousuke Tsuneoka, Kenkichi Takase, Staci J. Kim, Jinhwan Choi, Aya Ikkyu, Manabu Abe, Kenji Sakimura, Masashi Yanagisawa, Hiromasa Funato. Differential Roles of Each Orexin Receptor Signaling in Obesity. iScience 2019, 20 , 1-13. https://doi.org/10.1016/j.isci.2019.09.003
  16. Kouichi Yamamoto, Rikuya Okui, Atsushi Yamatodani. Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice. Naunyn-Schmiedeberg's Archives of Pharmacology 2019, 392 (8) , 925-936. https://doi.org/10.1007/s00210-019-01646-x
  17. Ainoleena Turku, Teppo O. Leino, Lasse Karhu, Jari Yli‐Kauhaluoma, Jyrki P. Kukkonen, Erik A. A. Wallén, Henri Xhaard. Structure–Activity Relationships of 1‐Benzoylazulenes at the OX 1 and OX 2 Orexin Receptors. ChemMedChem 2019, 14 (9) , 965-981. https://doi.org/10.1002/cmdc.201900074
  18. Eugenie Nepovimova, Jana Janockova, Jan Misik, Stepan Kubik, Ales Stuchlik, Karel Vales, Jan Korabecny, Eva Mezeiova, Rafael Dolezal, Ondrej Soukup, Tereza Kobrlova, Ngoc Lam Pham, Thuy Duong Nguyen, Jan Konecny, Kamil Kuca. Orexin supplementation in narcolepsy treatment: A review. Medicinal Research Reviews 2019, 39 (3) , 961-975. https://doi.org/10.1002/med.21550
  19. Steven T. Szabo, Michael J. Thorpy, Geert Mayer, John H. Peever, Thomas S. Kilduff. Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy. Sleep Medicine Reviews 2019, 43 , 23-36. https://doi.org/10.1016/j.smrv.2018.09.006
  20. Ana Clementina Equihua-Benítez, René Drucker-Colín. Drug Discovery and Emerging Treatments for Sleep Disorders. 2019,,, 623-637. https://doi.org/10.1016/B978-0-12-813743-7.00041-4
  21. . Handbook of Sleep Research. 2019,,https://doi.org/
  22. Jyrki P. Kukkonen. Pharmacology of Orexin/Hypocretin Receptors. 2019,,, 31-68. https://doi.org/10.1016/B978-0-12-813751-2.00002-4
  23. . The Orexin/Hypocretin System. 2019,,https://doi.org/
  24. Lucie Barateau, Yves Dauvilliers. Recent advances in treatment for narcolepsy. Therapeutic Advances in Neurological Disorders 2019, 12 , 175628641987562. https://doi.org/10.1177/1756286419875622
  25. Miguel Meira e Cruz, Sérgio Matoso Laranjo, Isabel Rocha. Hypothalamic Control of Sleep-Wake Circadian Cycle. 2018,,https://doi.org/10.5772/intechopen.79899
  26. , . Hypothalamus in Health and Diseases. 2018,,https://doi.org/10.5772/intechopen.69694
  27. 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. Investigation of New Orexin 2 Receptor Modulators Using In Silico and In Vitro Methods. Molecules 2018, 23 (11) , 2926. https://doi.org/10.3390/molecules23112926
  28. Maiju K. Rinne, Teppo O. Leino, Ainoleena Turku, Pauli M. Turunen, Yana Steynen, Henri Xhaard, Erik A.A. Wallén, Jyrki P. Kukkonen. Pharmacological characterization of the orexin/hypocretin receptor agonist Nag 26. European Journal of Pharmacology 2018, 837 , 137-144. https://doi.org/10.1016/j.ejphar.2018.09.003
  29. Laura A. Grafe, Seema Bhatnagar. Orexins and stress. Frontiers in Neuroendocrinology 2018, 51 , 132-145. https://doi.org/10.1016/j.yfrne.2018.06.003
  30. Teppo O. Leino, Ainoleena Turku, Jari Yli-Kauhaluoma, Jyrki P. Kukkonen, Henri Xhaard, Erik A.A. Wallén. Azulene-based compounds for targeting orexin receptors. European Journal of Medicinal Chemistry 2018, 157 , 88-100. https://doi.org/10.1016/j.ejmech.2018.07.040
  31. Jessica A Boyette-Davis, Saiyun Hou, Salahadin Abdi, Patrick M Dougherty. An updated understanding of the mechanisms involved in chemotherapy-induced neuropathy. Pain Management 2018, 8 (5) , 363-375. https://doi.org/10.2217/pmt-2018-0020
  32. Satoshi Toyama, Naohito Shimoyama, Yugo Tagaito, Hiroshi Nagase, Tsuyoshi Saitoh, Masashi Yanagisawa, Megumi Shimoyama. Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats. Anesthesiology 2018, 128 (5) , 992-1003. https://doi.org/10.1097/ALN.0000000000002161
  33. Shinichi Takenoshita, Noriaki Sakai, Yuhei Chiba, Mari Matsumura, Mai Yamaguchi, Seiji Nishino. An overview of hypocretin based therapy in narcolepsy. Expert Opinion on Investigational Drugs 2018, 27 (4) , 389-406. https://doi.org/10.1080/13543784.2018.1459561
  34. Lasse Karhu, Janne Weisell, Pauli M. Turunen, Teppo O. Leino, Henri Pätsi, Henri Xhaard, Jyrki P. Kukkonen, Erik A.A. Wallén. Stapled truncated orexin peptides as orexin receptor agonists. Peptides 2018, 102 , 54-60. https://doi.org/10.1016/j.peptides.2018.02.004
  35. James B Jaggard, Bethany A Stahl, Evan Lloyd, David A Prober, Erik R Duboue, Alex C Keene. Hypocretin underlies the evolution of sleep loss in the Mexican cavefish. eLife 2018, 7 https://doi.org/10.7554/eLife.32637
  36. Sayaka Ohrui, Naoshi Yamamoto, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase. Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity. Bioorganic & Medicinal Chemistry Letters 2018, 28 (4) , 774-777. https://doi.org/10.1016/j.bmcl.2017.12.069
  37. Birgitte R. Kornum, Stine Knudsen, Hanna M. Ollila, Fabio Pizza, Poul J. Jennum, Yves Dauvilliers, Sebastiaan Overeem. Narcolepsy. Nature Reviews Disease Primers 2017, 3 (1) https://doi.org/10.1038/nrdp.2016.100
  38. Sarah W. Black, Michael D. Schwartz, Tsui-Ming Chen, Marius C. Hoener, Thomas S. Kilduff. Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics. Biological Psychiatry 2017, 82 (9) , 623-633. https://doi.org/10.1016/j.biopsych.2016.10.012
  39. Christoph Boss, Catherine Roch. Orexin research: patent news from 2016. Expert Opinion on Therapeutic Patents 2017, 27 (10) , 1123-1133. https://doi.org/10.1080/13543776.2017.1344221
  40. Lucie Barateau, Roland Liblau, Christelle Peyron, Yves Dauvilliers. Narcolepsy Type 1 as an Autoimmune Disorder: Evidence, and Implications for Pharmacological Treatment. CNS Drugs 2017, 31 (10) , 821-834. https://doi.org/10.1007/s40263-017-0464-6
  41. Shinichi Takenoshita, Seiji Nishino. Pharmacologic Management of Excessive Daytime Sleepiness. Sleep Medicine Clinics 2017, 12 (3) , 461-478. https://doi.org/10.1016/j.jsmc.2017.03.019
  42. Ana Clementina Equihua-Benítez, Khalil Guzmán-Vásquez, René Drucker-Colín. Understanding sleep-wake mechanisms and drug discovery. Expert Opinion on Drug Discovery 2017, 12 (7) , 643-657. https://doi.org/10.1080/17460441.2017.1329818
  43. Lihang Yao, Andres D. Ramirez, Anthony J. Roecker, Steven V. Fox, Jason M. Uslaner, Sean M. Smith, Robert Hodgson, Paul J. Coleman, John J. Renger, Christopher J. Winrow, Anthony L. Gotter. The dual orexin receptor antagonist, DORA-22, lowers histamine levels in the lateral hypothalamus and prefrontal cortex without lowering hippocampal acetylcholine. Journal of Neurochemistry 2017, 142 (2) , 204-214. https://doi.org/10.1111/jnc.14055
  44. Ainoleena Turku, Maiju K. Rinne, Gustav Boije af Gennäs, Henri Xhaard, Dan Lindholm, Jyrki P. Kukkonen, . Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity. PLOS ONE 2017, 12 (6) , e0178526. https://doi.org/10.1371/journal.pone.0178526
  45. Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Hiromu Tominaga, Yukiko Ishikawa, Naoto Hosokawa, Shinobu Ambai, Yuki Kawabe, Shuntaro Uchida, Ryo Nakajima, Tsuyoshi Saitoh, Takeshi Kanda, Kaspar Vogt, Takeshi Sakurai, Hiroshi Nagase, Masashi Yanagisawa. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proceedings of the National Academy of Sciences 2017, 114 (22) , 5731-5736. https://doi.org/10.1073/pnas.1700499114
  46. Ulf Kallweit, Claudio L. Bassetti. Pharmacological management of narcolepsy with and without cataplexy. Expert Opinion on Pharmacotherapy 2017, 18 (8) , 809-817. https://doi.org/10.1080/14656566.2017.1323877
  47. Sarah Wurts Black, Akihiro Yamanaka, Thomas S. Kilduff. Challenges in the development of therapeutics for narcolepsy. Progress in Neurobiology 2017, 152 , 89-113. https://doi.org/10.1016/j.pneurobio.2015.12.002
  48. Laura A. Grafe, Darrell Eacret, Sandra Luz, Anthony L. Gotter, John J. Renger, Chris J. Winrow, Seema Bhatnagar. Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress. Neuroscience 2017, 348 , 313-323. https://doi.org/10.1016/j.neuroscience.2017.02.038
  49. Satoshi Toyama, Naohito Shimoyama, Megumi Shimoyama. The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain. Neuropeptides 2017, 61 , 95-100. https://doi.org/10.1016/j.npep.2016.12.007
  50. B.T. Shireman, M.A. Letavic. Orexin Receptor Antagonists. 2017,,, 225-279. https://doi.org/10.1016/B978-0-12-409547-2.12442-4
  51. . Comprehensive Medicinal Chemistry III. 2017,,https://doi.org/
  52. Yohei Sagawa, Masatoshi Sato, Noriaki Sakai, Sachiko Chikahisa, Shintaro Chiba, Takashi Maruyama, Junki Yamamoto, Seiji Nishino. Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice. Neuropharmacology 2016, 110 , 268-276. https://doi.org/10.1016/j.neuropharm.2016.07.013
  53. Lucie Barateau, Régis Lopez, Yves Dauvilliers. Management of Narcolepsy. Current Treatment Options in Neurology 2016, 18 (10) https://doi.org/10.1007/s11940-016-0429-y
  54. Lucie Barateau, Régis Lopez, Yves Dauvilliers. Treatment Options for Narcolepsy. CNS Drugs 2016, 30 (5) , 369-379. https://doi.org/10.1007/s40263-016-0337-4
  55. Alexander Heifetz, Matteo Aldeghi, Ewa I. Chudyk, Dmitri G. Fedorov, Mike J. Bodkin, Philip C. Biggin. Using the fragment molecular orbital method to investigate agonist–orexin-2 receptor interactions. Biochemical Society Transactions 2016, 44 (2) , 574-581. https://doi.org/10.1042/BST20150250
  56. Laura H. Jacobson, Sui Chen, Sanjida Mir, Daniel Hoyer. Orexin OX2 Receptor Antagonists as Sleep Aids. 2016,,, 105-136. https://doi.org/10.1007/7854_2016_47
  57. , . Behavioral Neuroscience of Orexin/Hypocretin. 2017,,https://doi.org/10.1007/978-3-319-57535-3

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