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

Volumn 53, Issue 14, 2010, Pages 5320-5332

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

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

[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; BENZOXAZOLE DERIVATIVE; MK 4305; OREXIN 1 RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; DRUG ACTIVITY; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; HUMAN; HUMAN CELL; INSOMNIA; MALE; NONHUMAN; RAT;

ANIMALS; AZEPINES; BIOLOGICAL AVAILABILITY; CHO CELLS; CRICETINAE; CRICETULUS; DOGS; HUMANS; MALE; MICROSOMES, LIVER; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RATS, TRANSGENIC; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, NEUROPEPTIDE; SLEEP; SLEEP INITIATION AND MAINTENANCE DISORDERS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TELEMETRY; TRIAZOLES; WAKEFULNESS;

EID: 77954731181     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100541c     Document Type: Article

References (68)

1. Passarella, S.; Duong, M.-T. Diagnosis and treatment of insomnia Am. J. Health-Syst. Pharm. 2008, 65, 927-934
2. Daley, M.; Morin, C. M.; LeBlanc, M.; Grégoire, J. P.; Savard, J.; Baillargeon, L. Insomnia and its relationship to health-care utilization, work absenteeism, productivity and accidents Sleep Med. 2009, 10, 427-438
3. Sullivan, S. S.; Guilleminault, C. Emerging drugs for insomnia: new frontiers for old and new targets Expert Opin. Emerging Drugs 2009, 14, 411-422
4. Renger, J. J. Overview of experimental and conventional pharmacological approaches in the treatment of sleep and wake disorders Curr. Top. Med. Chem. 2008, 8, 937-953
5. Wafford, K. A.; Ebert, B. Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time Nature Rev. Drug Discovery 2008, 7, 530-540
6. FDA Requests Label Change for All Sleep Disorder Drug Products. FDA News Release P07045, March 14, 2007; http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2007/ucm108868.htm.
7. Palomer, A.; Prinep, M.; Guglietta, A. Recent advances in the treatment of insomnia Annu. Rep. Med. Chem. 2007, 42, 63-80
8. Borja, N. L.; Daniel, K. L. Ramelteon for the treatment of insomnia Clin. Ther. 2006, 28, 1540-1555
9. Sateia, M. J.; Kirby-Long, P.; Taylor, J. L. Efficacy and clinical safety of ramelteon: an evidence-based review Sleep Med. Rev. 2008, 12, 319-332
10. For a compilation of investigations carried out to identify the orexin system and define its physiological roles, see: Hypocretins: Integrators of Physiological Functions; de Lecea, L.; Sutcliffe, J. G., Eds.; Springer: New York, 2005.
11. De Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.-B.; Foye, P. E.; Danielson, P. E.; Fukuhara, C.; Battenberg, E. L. F.; Gautvik, V. T.; Bartlett, F. S., II; Frankel, W. N.; Van Den Pol, A. N.; Bloom, F. E.; Gautvik, K. M.; Sutcliffe, J. G. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 322-327
12. Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.; Tanaka, H.; Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.; Wilson, S.; Arch, J. R. S.; Buckingham, R. E.; Haynes, A. C.; Carr, S. A.; Annan, R. S.; McNulty, D. E.; Liu, W.; Terrett, J. A.; Elshourbagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G-protein receptors that regulate feeding behavior Cell 1998, 92, 573-585
13. Chemelli, R. M.; Willie, J. T.; Sinton, C. M.; Elmquist, J. K.; Scammell, T.; Lee, C.; Richardson, J. A.; Williams, S. C.; Xiong, Y.; Kisanuki, Y.; Fitch, T. E.; Nakazato, M.; Hammer, R. E.; Saper, C. B.; Yanagisawa, M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation Cell 1999, 98, 437-451
14. Willie, J. T.; Chemelli, R. M.; Sinton, C. M.; Tokita, S.; Williams, S. C.; Kisanuki, Y. Y.; Marcus, J. N.; Lee, C.; Elmquist, J. K.; Kohlmeier, K. A.; Leonard, C. S.; Richardson, J. A.; Hammer, R. E.; Yanagisawa, M. Distinct narcolepsy syndromes in orexin receptor 2 and orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes Neuron 2003, 38, 715-730
15. Lin, L.; Faraco, F.; Li, R.; Kadotani, H.; Rogers, W.; Lin, X.; Qiu, X.; de Jong, P. J.; Nishino, S.; Mignot, E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin receptor 2 gene Cell 1999, 98, 365-376
16. Thannickal, T. C.; Moore, R. Y.; Nienhuis, R.; Ramanathan, L.; Gulyani, S.; Aldrich, M.; Cornford, M.; Siegel, J. M. Reduced number of hypocretin neurons in human narcolepsy Neuron 2000, 27, 469-474
17. Crocker, A.; Espana, R. A.; Papadopoulon, M.; Saper, C. B.; Faraco, J.; Sakurai, T.; Honda, M.; Mignot, E.; Scammell, T. E. Concomitant loss of dynorphin, Narp and orexin in narcolepsy Neurology 2005, 65, 1184-1188
18. Blouin, A. M.; Thannickal, T. E.; Worley, P. F.; Baraban, J. M.; Reti, I. M.; Siegel, J. M. Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy Neurology 2005, 65, 1189-1192
19. Akanmu, M. A.; Honda, K. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats Brain Res. 2005, 1048, 138-145
20. Selbach, O.; Eriksson, K. S.; Haas, H. L. Drugs to interfere with orexins (hypocretins) Drug News Perspect. 2003, 16, 669-681
21. Baumann, C. R.; Bassetti, C. L. Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter Sleep Med. Rev. 2005, 9, 253-268
22. Boss, C.; Brisbare-Roch, C.; Jenck, F.; Aissaoui, H.; Koberstein, R.; Sifferlen, T.; Weller, T. Orexin receptor antagonism: A new principle in neuroscience Chemia 2008, 62, 974-979
23. Boss, C.; Brisbare-Roch, C.; Jenck, F. Biomedical application of orexin/hypocretin receptor ligands in neuroscience J. Med. Chem. 2009, 52, 891-903
24. 2R) antagonists Bioorg. Med. Chem. Lett. 2004, 14, 4225-4229
25. Bingham, M. J.; Cai, J.; Deehan, M. R. Eating, sleeping and rewarding: orexin receptors and their antagonists Curr. Opin. Drug Discovery Dev. 2006, 9, 551-559
26. Cai, J.; Cooke, F. E.; Sherborne, B. S. Antagonists of the orexin receptors Expert Opin. Ther. Patents 2006, 16, 631-646
27. Roecker, A. J.; Coleman, P. J. Orexin receptor antagonists: Medicinal chemistry and therapeutic potential Curr. Top. Med. Chem. 2008, 8, 977-987
28. Bergman, J. M.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.; Reiss, D. R.; Ransom, R. W.; Harrell, C. M.; Pettibone, D. J.; Lemaire, W.; Murphy, K. L.; Li, C.; Preuksaritanont, T.; Winrow, C. J.; Renger, J. J.; Koblan, K. S.; Hartman, G. D.; Coleman, P. J. Proline bis-amides as potent dual orexin receptor antagonists Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430
29. Cole, A. G.; Stroke, I. L.; Qin, L.-Q.; Hussain, Z.; Simhadri, S.; Brescia, M.-R.; Waksmunski, F. S.; Strohl, B.; Tellew, J. E.; Williams, J. P.; Saunders, J.; Appell, K. C.; Henderson, I.; Webb, M. L. Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists Bioorg. Med. Chem. Lett. 2008, 18, 5420-5423
30. Aissaoui, H.; Koberstain, R.; Zumbrunn, C.; Gatfield, J.; Brisbane-Roch, C.; Jenck, F.; Treiber, A.; Boss, C. N -Glycine-sulfonamides as potent dual orexin 1/orexin 2 receptor antagonists Bioorg. Med. Chem. Lett. 2008, 18, 5729-5733
31. Sifferlen, T.; Boss, C.; Cottreel, E.; Koberstain, R.; Gude, M.; Aissaoui, H.; Weller, T.; Gatfield, J.; Brisbane-Roch, C.; Jenck, F. Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists Bioorg. Med. Chem. Lett. 2010, 20, 1539-1542
32. Coleman, P. J.; Renger, J. J. Orexin receptor antagonists: a review of promising compounds patented since 2006 Expert Opin. Ther. Patents 2010, 20, 307-324
33. Dugovic, C.; Shelton, J. E.; Aluisio, L. E.; Fraser, I. C.; Jiang, X.; Sutton, S. W.; Bonaventure, P.; Yun, S.; Li, X.; Lord, B.; Dvorak, C. A.; Carruthers, N. I.; Lovenberg, T. W. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in rat J. Pharmacol. Exp. Ther. 2009, 330, 141-152
34. Owen, R. T.; Casten~er, R.; Bolós, J.; Estivill, C. Almorexant Drugs Future 2009, 34, 5-10
35. Brisbare-Roch, C.; Dingemanse, J.; Koberstein, R.; Hoever, P.; Aissaoui, H.; Flores, S.; Mueller, C.; Nayler, O.; van Gerven, J.; de Haas, S. L.; Hess, P.; Qiu, C.; Buchmann, S.; Scherz, M.; Weller, T.; Fischli, W.; Clozel, M.; Jenck, F. Promotion of sleep by targeting the orexin system in rats, dogs and humans Nature Med. 2007, 13, 150-155
36. New Data On Orexin Receptor Antagonist Almorexant Shows Therapeutic Potential To Restore Normal Physiological Sleep In Insomnia Patients. Medical News Today Sep 04, 2007; http://www.medicalnewstoday.com/articles/81354.php.
37. Following the observation of preclinical toxicity, GSK entered into a deal with Actelion to jointly develop and market Almorexant, see: http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next= bioWorldHeadlines-article&forceid=48183
38. Merck 2008 Annual Business Briefing - Final. Goliath Business News Dec 9, 2008; http://goliath.ecnext.com/coms2/gi-0199-9773483/Merck-2008-Annual- Business-Briefing.html.
39. A Long Term Safety Study of MK4305 in Patients With Primary Insomnia ClinicalTrials.gov 2009; http://clinicaltrials.gov/ct2/show/NCT01021813
40. 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.; Reiss, D. R.; Harrell, C. M.; Kraus, R. L.; Li, Y.; Garson, S. L.; Doran, S. M.; Prueksaritanont, T.; Li, C.; Winrow, C. J.; Koblan, K. S.; Renger, J. J.; Coleman, P. J. Discovery of a potent, CNS-penetrant orexin receptor antagonist based on an N,N -disubstituted-1,4-diazepane scaffold that promotes sleep in rats ChemMedChem 2009, 4, 1069-1074
41. Further investigations by NMR spectroscopy, X-ray crystallography and molecular modeling revealed that 4 exists both in the solid state and solution in an unusual horseshoe- or U-shaped conformation characterized by a p-stacking interaction between the quinazoline and phenyl rings. Cox, C. D.; McGaughey, G. B.; Bogusky, M. J.; Whitman, D. B.; Ball, R. G.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Conformational analysis of N,N -disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding Bioorg. Med. Chem. Lett. 2009, 19, 2997-3001 We recently reported that bridged diazepane analogues, whose design and synthesis was inspired by the low energy conformation of 4, are also potent DORAs that promote sleep in rats, see
42. Coleman, P. J.; Schreier, J. D.; McGaughey, G. B.; Bogusky, M. J.; Cox, C. D.; Hartman, G. D.; Ball, R. G.; Harrell, C. M.; Reiss, D. R.; Prueksaritanont, T.; Winrow, C. J.; Renger, J. J. Design and synthesis of conformationally constrained N, N -disubstituted-1,4-diazepanes as potent orexin receptor antagonists Bioorg. Med. Chem. Lett. 2010, 20, 2311-2315
43. Coleman, P. J.; Schreier, J. D.; Roecker, A. J.; Mercer, S. P.; McGaughey, G. B.; Cox, C. D; Hartman, G. D.; Harrell, C. M.; Reiss, D. R.; Garson, S. L.; Anderson, W. B.; Prueksaritanont, T.; Winrow, C. J.; Renger, J. J. Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent orexin receptor antagonists with sleep-promoting activity in the rat. Bioorg. Med. Chem. Lett. 2010, DOI: 10.1016/j.bmcl.2010.05.047
44. Other vehicles studied included 0.5% aqueous methylcellulose, 10% Tween 80 in water, and 0.1 M citric acid.
45. The position of oxidation is not known. For simplicity in visualization, oxidation at the 7-position of the core is shown.
46. A large number of the cores made during this effort are described in Coleman, P. J.; Cox, C. D.; Roecker, A. J. Discovery of Dual Orexin Receptor Antagonists (DORAs) for the Treatment of Insomnia. Curr. Top. Med. Chem. in press.
47. Dog pharmacokinetic "cassettes" where utilized wherein 5-6 test compounds plus a standard were dosed IV in DMSO, with the goal being to identify compounds with reduced IV clearance. Promising analogues were then repeated as both IV and PO singles. In general, the data obtained in cassette format was reproduced well in the IV singles. Though some exceptions were noted, this strategy led to a number of diazepanes with improved bioavailability.
48. Poppelsdorf, F.; Myerly, R. C. A novel synthesis of homopiperazine and its monomethyl derivatives J. Org. Chem. 1961, 26, 131-134
49. Benalil, A.; Guerin, A.; Carboni, B.; Vaultier, M. Synthesis of 2,3,6,7-tetrahydro- and 2,3,4,5,6,7-hexahydro-1 H -1,4-diazepines via a tandem Michael-type addition-intramolecular aza-Wittig sequence J. Chem. Soc., Perkin Trans 1 1993, 1061-1064
50. Subsequent to our work reported herein, an efficient synthesis of the mono-protected 5-methyldiazepane core was reported, see: Wlodarczyk, N.; Gilleron, P.; Millet, R.; Houssin, R.; Hénichart, J.-P. Synthesis of 1,4-diazepin-5-ones under microwave irradiation and their reduction products Tetrahedron Lett. 2007, 48, 2583-2586
51. Leonard, J.; Lygo, B.; Procter, G. Advanced Practical Organic Chemistry; Blackie: New York, 1995; p 6.
52. i = 8.5 nM, corresponding to 8- and 18-fold losses in potency, respectively, relative to the (R)-antipode. We have confirmed the stereochemistry in the active series is (R) by both X-ray crystallography using anomalous dispersion, as well as an asymmetric synthesis starting from the chiral pool.
53. 1R potency.
54. We have found that a vehicle of 20% TPGS in water to be an excellent vehicle for improving exposure of BCS class II molecules such as the diazepanes described herein and is also highly compatible with our sleep studies. For a study of the effects that TPGS has on oral absorption, see: Varma, M. V. S.; Panchagnula, R. Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo Eur. J. Pharm. Sci. 2005, 25, 445-453
55. Brain, plasma, and CSF concentrations were measured following a 30 min continuous IV infusion of 10 at 0.25, 0.75, and 1.5 mg/kg in 25% hydroxypropyl-β-cyclodextrin.
56. Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development Chem. Res. Toxicol. 2004, 17, 3-16
57. Kumar, S.; Baillie, T. A. Minimizing metabolic activation in drug discovery in Handbook of Drug Metabolism, 2nd ed.; Pearson, P. G.; Wienkers, L. C., Eds.; Informa Healthcare: New York, 2009; Chapter 23.
58. See the Experimental Section for details.
59. GSH-adducts were identified that had a mass spectral signal corresponding to loss of the fluorine atom, suggesting the fluoroquinazoline as a site of bioactivation. The GSH-adduct/IS ratio of compound 4 is 5.0, suggesting that the nonfluorinated quinazoline also likely undergoes bioactivation and subsequent trapping with GSH.
60. As with diazepane DORA 4, solution NMR studies of 3 indicate a very complex situation with several low energy conformations in equilibrium. Studies are underway to characterize the low energy conformations of 3 and how they fit with our proposed bioactive conformation model. (25)
61. Brain, plasma, and CSF concentrations were measured following a 30 min continuous IV infusion of 3 at 0.25, 0.75, and 1.5, and 2.0 mg/kg in 25% hydroxypropyl-β-cyclodextrin. Brain/plasma ratios ranged from 0.6-1.2 and the CSF/plasma ratios ranged from 0.007-0.017. When dosed at 10 mg/kg PO in 20% TPGS, at 1 h post dose the brain/plasma ratio was 0.7 and the CSF/plasma ratio was 0.007.
62. A manuscript in preparation will describe the pharmacology of 3 in more detail, including analysis of its dose-dependent effects on sleep in rats, dogs, and monkeys. Winrow, C. J. unpublished results.
63. The identities of 14 - 16 were confirmed by independent synthesis.
64. Kunapuli, P.; Ransom, R.; Murphy, K. L.; Pettibone, D. J.; Kerby, J.; Grimwood, S.; Zuck, P.; Hodder, P.; Lacson, R.; Hoffman, I.; Inglese, J.; Strulovici, B. Development of an intact cell reporter gene β-lactamase assay for G-protein coupled receptors for high-throughput screening Anal. Biochem. 2003, 314, 16-29
65. Mosser, S. D.; Stanley, L.; Gaul, S. L.; Bednar, B.; Koblan, K. S.; Bednar, R. A. Automation of in vitro dose-inhibition assays using the Tecan Genesis and an integrated software package to support the drug discovery process J. Assoc. Lab. Autom. 2003, 8, 54-62
66. Alvarino, F.; Monti, J. M.; Jantos, H.; Monti, D. Effect of SX-3228, a selective ligand for the BZ1 receptor, on sleep and waking during the light-dark cycle in the rat Braz. J. Med. Biol. Res. 1999, 32, 1007-1014
67. Monti, J. M.; Jantos, H.; Monti, D. Increase in waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition: prevention with GABAA or adenosine A1 receptor agonists Behav. Brain Res. 2001, 123, 23-35
68. Lazer, E. S.; Miao, C. K.; Wong, H.-C.; Sorcek, R.; Spero, D. M.; Gilman, A.; Pal, K.; Behnke, M.; Graham, A. G.; Watrous, J. M.; Homon, C. A.; Nagel, J.; Shah, A.; Guindon, Y.; Farina, P. R.; Adams, J. Benzoxazolamines and benzothiazolamines: Potent, enantioselective inhibitors of leukotriene biosynthesis with a novel mechanism of action J. Med. Chem. 1994, 37, 913-923