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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

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Departments of Medicinal Chemistry
Chemistry Modeling and Informatics
§ In Vitro Sciences
Depression and Circadian Disorders
Drug Metabolism
Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486
*To whom correspondence should be addressed. Phone: + 1-215-652-2411. Fax: + 1-215-652-7310. E-mail: [email protected]
Cite this: J. Med. Chem. 2010, 53, 14, 5320–5332
Publication Date (Web):June 21, 2010
Copyright © 2010 American Chemical Society

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    Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.

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    Experimental procedures for compounds 813, as well as reproductions of the 1H and 13C NMR spectra for key compounds. This material is available free of charge via the Internet at

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