[(7R)-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
Suvorexant
may23,2013
A panel of experts at the US Food and Drug Administration has recommended Merck & Co’s insomnia drug suvorexant when given in lower dosages but rejected the higher dose that the company was seeking.———read more at
Suvorexant (MK-4305) is a dual orexin receptor antagonist in development by Merck & Co.[1][2][3] Suvorexant works by turning off wakefulness rather than by inducing sleep.[4] It is not currently approved for commercial use, but it has completed three Phase III trials.[5]The recent FDA review showed that the drug is associated with increased somnolence the next day and users of higher doses had an increased rate of suicidal ideation. [6] It is one of two such compounds currently in development, the other being GlaxoSmithKline‘s SB-649,868.
- Cox, Christopher D.; Breslin, Michael J.; Whitman, David B.; Schreier, John D.; McGaughey, Georgia B.; Bogusky, Michael J.; Roecker, Anthony J.; Mercer, Swati P. 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-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia”. Journal of Medicinal Chemistry 53 (14): 5320–32. doi:10.1021/jm100541c. PMID 20565075. edit
- Baxter, Carl A.; Cleator, Ed; Brands, Karel M. J.; Edwards, John S.; Reamer, Robert A.; Sheen, Faye J.; Stewart, Gavin W.; Strotman, Neil A. et al. (2011). “The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder”. Organic Process Research & Development 15 (2): 367–75.doi:10.1021/op1002853. edit
- Winrow, Christopher J.; Gotter, Anthony L.; Cox, Christopher D.; Doran, Scott M.; Tannenbaum, Pamela L.; Breslin, Michael J.; Garson, Susan L.; Fox, Steven V. et al. (2011). “Promotion of Sleep by Suvorexant—A Novel Dual Orexin Receptor Antagonist”.Journal of Neurogenetics 25 (1–2): 52–61. doi:10.3109/01677063.2011.566953.PMID 21473737. edit
- Kahn, Howie (June 1, 2012). “Sleep Better”. In Koerth-Baker, Maggie. 32 Innovations That Will Change Your Tomorrow. New York Times. Retrieved November 29, 2012.
- Three completed trials:
- ClinicalTrials.gov NCT01097629 Safety and Efficacy Study in Primary Insomnia Patients-Study B (4305-029)
- ClinicalTrials.gov NCT01021813 A Long Term Safety Study of MK4305 in Patients With Primary Insomnia (4305-009 AM3)
- ClinicalTrials.gov NCT01097616 Safety and Efficacy Study in Primary Insomnia Patients- Study A (4305-028)
- http://www.usatoday.com/story/news/nation/2013/05/20/fda-merck-insomnia-drug/2326921/
Enantioselective Synthesis of a Dual Orexin Receptor Antagonist.
Org. Lett. 2012; 14: 3458-3461
Orexins A and B are excitatory neuropeptides that stimulate wakefulness. Suvorexant is a dual orexin receptor antagonist that is in phase III clinical trials for the treatment of insomnia. The key step in the asymmetric synthesis depicted is a tandem enzymatic transamination–annulation sequence (F → G → H).
A previous synthesis of suvorexant (N. A. Strotman et al. J. Am. Chem. Soc. 2011, 133, 8362) involved an asymmetric Ru-catalyzed reductive amination in the construction of the diazepane ring. The present route benefits from the circumvention of transition-metal catalysis and dichloromethane as solvent.
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