The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
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
Open accessAbstract
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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Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Williams, S. C., Richardson, J. A., Kozlowski, G. P., Wilson, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)80949-6 · Cited by 5,501
The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity
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., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.322 · Cited by 3,878
Narcolepsy in orexin Knockout Mice
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., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)81973-x · Cited by 3,095
Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., de Jong, P. J., Nishino, S., & Mignot, E. (1999) · Cell · doi:10.1016/s0092-8674(00)81965-0 · Cited by 2,613
Reduced Number of Hypocretin Neurons in Human Narcolepsy
Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., & Siegel, J. M. (2000) · Neuron · doi:10.1016/s0896-6273(00)00058-1 · Cited by 2,089
Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., & Baillie, T. A. (2004) · Chemical Research in Toxicology · doi:10.1021/tx034170b · Cited by 706
Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice
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., et al. (2003) · Neuron · doi:10.1016/s0896-6273(03)00330-1 · Cited by 645
Promotion of sleep by targeting the orexin system in rats, dogs and humans
Brisbare-Roch, C., Dingemanse, J., Koberstein, R., Hoever, P., Aissaoui, H., Flores, S., Mueller, C., Nayler, O., van Gerven, J., de Haas, S. L., et al. (2007) · Nature Medicine · doi:10.1038/nm1544 · Cited by 573
Daley, M., Morin, C. M., LeBlanc, M., Grégoire, J. P., Savard, J., & Baillargeon, L. (2009) · Sleep Medicine · doi:10.1016/j.sleep.2008.04.005 · Cited by 440
Varma, M. V. S., & Panchagnula, R. (2005) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2005.04.003 · Cited by 361
Cited by
Click Chemistry: 1,2,3‐Triazoles as Pharmacophores
Agalave, S. G., Maujan, S. R., & Pore, V. S. (2011) · Chemistry – An Asian Journal · doi:10.1002/asia.201100432 · Cited by 1,305
The role of orexin in motivated behaviours
Sakurai, T. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3837 · Cited by 464
Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery
Atkin, T., Comai, S., & Gobbi, G. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014381 · Cited by 391
Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials
Herring, W. J., Connor, K. M., Ivgy-May, N., Snyder, E., Liu, K., Snavely, D. B., Krystal, A. D., Walsh, J. K., Benca, R. M., Rosenberg, R., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.10.003 · Cited by 300
Promotion of Sleep by Suvorexant—A Novel Dual Orexin Receptor Antagonist
Winrow, C. J., Gotter, A. L., Cox, C. D., Doran, S. M., Tannenbaum, P. L., Breslin, M. J., Garson, S. L., Fox, S. V., Harrell, C. M., Stevens, J., et al. (2011) · Journal of Neurogenetics · doi:10.3109/01677063.2011.566953 · Cited by 269
Self-citationHerring, W. J., Ceesay, P., Snyder, E., Bliwise, D., Budd, K., Hutzelmann, J., Stevens, J., Lines, C., & Michelson, D. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12035 · Cited by 185
The discovery of suvorexant, the first orexin receptor drug for insomnia
Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104837 · Cited by 128
Self-citationOrexins and fear: Implications for the treatment of anxiety disorders
Flores, Á., Saravia, R., Maldonado, R., & Berrendero, F. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.06.005 · Cited by 102
Roth, B. L., & Kroeze, W. K. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.654764 · Cited by 88
Overview of orexin/hypocretin system
Mieda, M., & Sakurai, T. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59489-1.00002-1 · Cited by 64
Herring, W. J., Roth, T., Krystal, A. D., & Michelson, D. (2019) · Journal of Sleep Research · doi:10.1111/jsr.12782 · Cited by 53
Metadata
- Authors
- Cox, C. D., Breslin, M. J., Whitman, D. B., Schreier, J. D., McGaughey, G. B., Bogusky, M. J., Roecker, A. J., Mercer, S. P., Bednar, R. A., Lemaire, W., Bruno, J. G., Reiss, D. R., Harrell, C. M., Murphy, K. L., Garson, S. L., Doran, S. M., Prueksaritanont, T., Anderson, W. B., Tang, C., Roller, S., Cabalu, T. D., Cui, D., Hartman, G. D., Young, S. D., Koblan, K. S., Winrow, C. J., Renger, J. J., & Coleman, P. J.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-06-21
- Volume
- 53
- Issue
- 14
- Pages
- 5320-5332
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2018441208
- Cited by
- 379
- References
- 34
- FWCI
- 27.57
- Type
- journal article
- Language
- en
- Open access
- green
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