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.


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.

DOI: 10.1021/jm100541c
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@article{Cox2010DiscoveryOT, title={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.}, author={Christopher D. Cox and Michael J. Breslin and David Whitman and John D. Schreier and Georgia B. McGaughey and Michael Bogusky and Anthony J. Roecker and Swati P Mercer and Rodney A. Bednar and Wei Lemaire and Joseph G Bruno and Duane R. Reiss and Charles Harrell and Kathy Murphy and Susan L. Garson and Scott M. Doran and Thomayant Prueksaritanont and W Brantley Anderson and Cuyue Tang and Shane A Roller and Tamara D Cabalu and Donghui Cui and George D. Hartman and Steven D Young and Ken S. Koblan and Christopher J Winrow and John Joseph Renger and Paul J. Coleman}, journal={Journal of medicinal chemistry}, year={2010}, volume={53 14}, pages={5320-32} }