MK-4305

MK-4305 (Suvorexant)
Description:
Ki: MK-4305 is a potent antagonist of OX1 receptor and OX2 receptor with Ki values of 0.55 nM and 0.35 nM, respectively [1].
Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) with partially overlapping nervous system distributions. As a dual orexin receptor (OXR) antagonist (DORA), suvorexant (MK-4305) has shown promise for the treatmen to finsomnias and sleep disorders.
In vitro: In vitro study showed that MK-4305 possesseed a clean ancillary profile (>10000-fold selectivity for OX2R) as determined by an MDS Pharma off-target screen of 170 enzymes, receptors, and ion channels [1].
In vivo: In a mice in-vivo study, suvorexant (25mg/kg) was tested in mice during the inactive phase (lights on) when sleep is naturally more prevalent and when orexin levels are normally low. It was found that suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4h after dosing. At the doses tested, suvorexant significantly decreased wake only during the first hour and IPSU did not affect wake time. These data suggest that OX2R preferring antagonists may have areduced tendency for perturbing NREM/REM architecture in comparison with DORAs [2].
Clinical trial: Suvorexant (trade name Belsomra) is marketed by Merck & Co. for the treatment of insomnia. It is effective for insomnia, at least for four weeks and as compared to a placebo. It was approved for sale by the U.S. Food & Drug Administration on August 13, 2014. The United States DEA has placed it on the list of schedule IV controlled substances. The drug became available in the United States on Tuesday, 3 February 2015 and Japan somewhere in November 2014 (http://en .wikipedia.org/wiki/Suvorexant).
Reference:
[1] Cox CD, Breslin MJ, Whitman DB, et al. 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. J Med Chem. 2010;53(14):5320-32.
[2] Hoyer D, Dürst T, Fendt M, Jacobson LH, Betschart C, Hintermann S, Behnke D, Cotesta S, Laue G, Ofner S, Legangneux E, Gee CE. Distinct effects of IPSU and suvorexant on mouse sleep architecture. Front Neurosci. 2013;7:235.

Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305).[Pubmed:21528938]

J Am Chem Soc. 2011 Jun 1;133(21):8362-71.

The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.

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.[Pubmed:20565075]

J Med Chem. 2010 Jul 22;53(14):5320-32.

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.