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

Citations Over TimeTop 10% of 2010 papers

Abstract

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.

Related Papers

• → Involvement of the Lateral Hypothalamic Peptide Orexin in Morphine Dependence and Withdrawal(2003)372 cited
• → A comparison of in vivo and in vitro methods for determining availability of iron from meals(1981)109 cited
• → The increasing doses of methotrexate pharmacokinetics after intravenous administration in rats - model selection(2019)3 cited
• Pharmacokinetics of monoclonal antibody HAb 18 and its F(ab^)_(2) and fab fragments in mice(1996)
• Pharmacokinetics and tissue distribution of Chuanhuning emuslion in rats(2014)