Discovery and development of orexin receptor antagonists as therapeutics for insomnia

British Journal of Pharmacology

Volumn 171, Issue 2, 2014, Pages 283-293

  Winrow, C J ^a   Renger, J J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

GABA; insomnia; orexin receptor antagonist; sleep

Indexed keywords

1 (2 METHYL 6 BENZOXAZOLYL) 3 (1,5 NAPHTHYRIDIN 4 YL)UREA; 1 (6,8 DIFLUORO 2 METHYL 4 QUINOLINYL) 3 (4 DIMETHYLAMINOPHENYL)UREA; 4 AMINOBUTYRIC ACID A RECEPTOR STIMULATING AGENT; ALMOREXANT; BENZODIAZEPINE DERIVATIVE; FILOREXANT; JNJ 1037049; JSK 1059865; OREXIN RECEPTOR ANTAGONIST; OREXIN RECEPTOR ANTAGONIST 22; RECEPTOR BLOCKING AGENT; SB 649868; SB 674042; SUVOREXANT; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; BINDING AFFINITY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TOLERABILITY; HUMAN; INSOMNIA; LATENT PERIOD; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; NONREM SLEEP; PRIORITY JOURNAL; REM SLEEP; REVIEW; SIGNAL TRANSDUCTION; SLEEP QUALITY; SLEEP TIME; TIME TO MAXIMUM PLASMA CONCENTRATION;

GABA; INSOMNIA; OREXIN RECEPTOR ANTAGONIST; SLEEP;

ACETAMIDES; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG DESIGN; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; HYPNOTICS AND SEDATIVES; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; ISOQUINOLINES; NEUROPEPTIDES; OREXIN RECEPTORS; SIGNAL TRANSDUCTION; SLEEP INITIATION AND MAINTENANCE DISORDERS;

EID: 84891275537     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12261     Document Type: Review

References (72)

1. American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, Fourth edn. Text Revision. American Psychiatric Association: Washington, DC.
2. Bergman JM, Roecker AJ, Mercer SP, Bednar RA, Reiss DR, Ransom RW, et al. (2008). Proline bis-amides as potent dual orexin receptor antagonists. Bioorg Med Chem Lett 18: 1425-1430. (Pubitemid 351227461)
3. Bettica P, Nucci G, Pyke C, Squassante L, Zamuner S, Ratti E, et al. (2012a). Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist. J Psychopharmacol 26: 1058-1070.
4. Bettica P, Squassante L, Groeger JA, Gennery B, Winsky-Sommerer R, Dijk DJ, (2012b). Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia. Neuropsychopharmacology 37: 1224-1233.
5. Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E, (2012c). The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 35: 1097-1104.
6. Beuckmann CT, Sinton CM, Williams SC, Richardson JA, Hammer RE, Sakurai T, et al. (2004). Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J Neurosci 24: 4469-4477. (Pubitemid 38608158)
7. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, et al. (2007). Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13: 150-155.
8. Brisbare-Roch C, Clozel M, Jenck F, (2008). Effects of repeated oral administration of the orexin receptor antagonist almorexant in male rats and dogs. Sleep 31: A38-A38.
9. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: 437-451. (Pubitemid 29402482)
10. Coleman PJ, Renger JJ, (2010). Orexin receptor antagonists: a review of promising compounds patented since 2006. Expert Opin Ther Pat 20: 307-324.
11. Coleman PJ, Schreier JD, Cox CD, Breslin MJ, Whitman DB, Bogusky MJ, et al. (2012). Discovery of [(2R,5R)-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: 415-424. 337.
12. Cox CD, Breslin MJ, Whitman DB, Schreier JD, McGaughey GB, Bogusky MJ, et al. (2010). Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methy l-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 53: 5320-5332.
13. Crocker A, Espana RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, et al. (2005). Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65: 1184-1188. (Pubitemid 41508208)
14. Di Fabio R, Pellacani A, Faedo S, Roth A, Piccoli L, Gerrard P, et al. (2011). Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders. Bioorg Med Chem Lett 21: 5562-5567.
15. Dugovic C, Shelton JE, Aluisio LE, Fraser IC, Jiang XH, Sutton SW, et al. (2009). Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther 330: 142-151.
16. Faedo S, Perdona E, Antolini M, Di FR, Merlo PE, Corsi M, (2012). Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists. Eur J Pharmacol 692: 1-9.
17. GlaxoSmithKline (2012). GlaxoSmithKline product pipeline. Available at: http://www.gsk.com/investors/product-pipeline.html (accessed 11/12/2012).
18. Gotter AL, Roecker AJ, Hargreaves R, Coleman PJ, Winrow CJ, Renger JJ, (2012a). Orexin receptors as therapeutic drug targets. Prog Brain Res 198: 163-188.
19. Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ, (2012b). International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 64: 389-420.
20. Gozzi A, Turrini G, Piccoli L, Massagrande M, Amantini D, Antolini M, et al. (2011). Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS ONE 6: e16406.
21. Grady SP, Nishino S, Czeisler CA, Hepner D, Scammell TE, (2006). Diurnal variation in CSF orexin-A in healthy male subjects. Sleep 29: 295-297. (Pubitemid 44019951)
22. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, et al. (2001). Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30: 345-354. (Pubitemid 32530580)
23. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, et al. (2000). A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96: 45-51.
24. Herring WJ, Connor K, Ivgy-May N, Snavely D, Snyder E, Liu K, et al. (2012a). Efficacy and safety of suvorexant, a dual orexin receptor antagonist, in patients with primary insomnia: results from two pivotal trials.
25. Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, et al. (2012b). Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 79: 2265-2274.
26. Herring WJ, Snyder E, Paradis E, Liu M, Snavely D, Roth T, et al. (2012c). Long term safety and efficacy of suvorexant in patients with primary insomnia. J Sleep Disord Res 35: A217. abstract 0641.
27. Hindmarch I, Legangneux E, Stanley N, Emegbo S, Dawson J, (2006). A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers. Br J Clin Pharmacol 62: 538-545. (Pubitemid 44571574)
28. Hoch M, Hoever P, Alessi F, Marjason J, Dingemanse J, (2011a). Pharmacokinetics and tolerability of almorexant in Japanese and Caucasian healthy male subjects. Pharmacology 88: 121-126.
29. Hoch M, Hoever P, Haschke M, Krahenbuhl S, Dingemanse J, (2011b). Food effect and biocomparison of two formulations of the dual orexin receptor antagonist almorexant in healthy male subjects. J Clin Pharmacol 51: 1116-1121.
30. Hoch M, Hay JL, Hoever P, de Kam ML, Te Beek ET, van Gerven JM, et al. (2012a). Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. Eur Neuropsychopharmacol 23: 107-117.
31. Hoch M, Hoever P, Alessi F, Theodor R, Dingemanse J, (2012b). Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects. Eur J Clin Pharmacol 69: 523-532.
32. Hoch M, Hoever P, Zisowsky J, Priestley A, Fleet D, Dingemanse J, (2012c). Absolute oral bioavailability of almorexant, a dual orexin receptor antagonist, in healthy human subjects. Pharmacology 89: 53-57.
33. Hoever P, de Haas SL, Dorffner G, Chiossi E, van Gerven JM, Dingemanse J, (2012a). Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J Psychopharmacol 26: 1071-1080.
34. Hoever P, Dorffner G, Benes H, Penzel T, Danker-Hopfe H, Barbanoj MJ, et al. (2012b). Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin Pharmacol Ther 91: 975-985.
35. Hoque R, Chesson AL Jr, (2009). Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem. J Clin Sleep Med 5: 471-476.
36. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ, (2004). Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol 141: 340-346. (Pubitemid 38250904)
37. de Lecea L, Kilduff TS, Peyron C, Gao XB, Foye PE, Danielson PE, et al. (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95: 322-327. (Pubitemid 28103952)
38. Li AH, Nattie E, (2010). Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol 588: 2935-2944.
39. Lieberman JAI, Neubauer DN, (2007). Understanding insomnia: diagnosis and management of a common sleep disorder. J Fam Pract 56: 35A-49A.
40. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin XY, et al. (1999). The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98: 365-376. (Pubitemid 29380571)
41. McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, et al. (2004). Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists. Bioorg Med Chem Lett 14: 4225-4229. (Pubitemid 38916941)
42. McElhinny CJ Jr, Lewin AH, Mascarella SW, Runyon S, Brieaddy L, Carroll FI, (2012). Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies. Bioorg Med Chem Lett 22: 6661-6664.
43. Malherbe P, Borroni E, Gobbi L, Knust H, Nettekoven M, Pinard E, et al. (2009). Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol 156: 1326-1341.
44. Mang GM, Durst T, Burki H, Imobersteg S, Abramowski D, Schuepbach E, et al. (2012). The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 35: 1625-1635.
45. Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M, (2009). Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 32: 351-360.
46. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. (2002). The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 59: 1553-1562.
47. Morgenthaler T, Kramer M, Alessi C, Friedman L, Boehlecke B, Brown T, et al. (2006). Practice parameters for the psychological and behavioral treatment of insomnia: an update. An american academy of sleep medicine report. Sleep 29: 1415-1419. (Pubitemid 44764666)
48. Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. (2007). Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 30: 1705-1711. (Pubitemid 350234749)
49. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E, (2000). Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355: 39-40. (Pubitemid 30072183)
50. Otmani S, Demazieres A, Staner C, Jacob N, Nir T, Zisapel N, et al. (2008). Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol 23: 693-705.
51. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. (2000). A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6: 991-997.
52. Porter RA, Chan WN, Coulton S, Johns A, Hadley MS, Widdowson K, et al. (2001). 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett 11: 1907-1910. (Pubitemid 32675315)
53. Renger JJ, Kern JT, (2011). Preface to the special issue 'Novel pharmaconeurogenetic approaches arising from progress in translational genetics. J Neurogenet 25: 117-119.
54. Renzulli C, Nash M, Wright M, Thomas S, Zamuner S, Pellegatti M, et al. (2011). Disposition and metabolism of [14C]SB-649868, an orexin 1 and 2 receptor antagonist, in humans. Drug Metab Dispos 39: 215-227.
55. Roehrs T, Roth T, (2012). Insomnia pharmacotherapy. Neurother 9: 728-738.
56. Roth T, (2007). A physiologic basis for the evolution of pharmacotherapy for insomnia. J Clin Psychiatry 68 (Suppl. 5): 13-18. (Pubitemid 46847823)
57. Rush CR, Armstrong DL, Ali JA, Pazzaglia PJ, (1998). Benzodiazepine- receptor ligands in humans: acute performance-impairing, subject-rated and observer-rated effects. J Clin Psychopharmacol 18: 154-165.
58. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573-585. (Pubitemid 28101119)
59. Scammell TE, Winrow CJ, (2011). Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51: 243-266.
60. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M, (2008). Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 4: 487-504.
61. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, et al. (2001). SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 132: 1179-1182. (Pubitemid 32234700)
62. Steiner MA, Lecourt H, Strasser DS, Brisbare-Roch C, Jenck F, (2011). Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-alpha1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. Neuropsychopharmacology 36: 848-856.
63. Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, et al. (2013). Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 36: 259-267.
64. Sunovion Pharmaceuticals Inc (2012). Lunesta product label. Available at: http://www.lunesta.com/PostedApprovedLabelingText.pdf (accessed 28/2/2013).
65. Taheri S, Sunter D, Dakin C, Moyes S, Seal L, Gardiner J, et al. (2000). Diurnal variation in orexin A immunoreactivity and prepro-orexin mRNA in the rat central nervous system 3. Neurosci Lett 279: 109-112. (Pubitemid 30055293)
66. Takeda Pharmaceuticals America Inc (2010). Rozerem product label. Available at: http://www.accessdata.fda.gov/drugsatfda-docs/label/2010/ 021782s011lbl.pdf (accessed 28/2/2013)
67. Thannickal TC, Siegel JM, Nienhuis R, Moore RY, (2003). Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy. Brain Pathol 13: 340-351. (Pubitemid 36975824)
68. Wilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, et al. (2010). British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol 24: 1577-1601.
69. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, et al. (2011). Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet 25: 52-61.
70. Winrow CJ, Gotter AL, Coleman PJ, Hargreaves R, Renger J, (2012a). Recent chronology of orexin pharmacology and its potential as a treatment for primary insomnia. In:, Rankovic Z, Bingham M, Nestler EJ, Hargreaves R, (eds). Drug Discovery for Psychiatric Disorders. The Royal Society of Chemistry: London, pp. 416-442.
71. Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, et al. (2012b). Pharmacological characterization of MK-6096-a dual orexin receptor antagonist for insomnia. Neuropharmacology 62: 978-987.
72. Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E, (2003). Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J Neurosci 23: 3555-3560. (Pubitemid 36531999)