Orexin Receptor Antagonists

Subsequent to the extensive medicinal chemistry exploration of Orexin antagonism, its utility in the treatment of sleep disorders in man has been reported recently. This important milestone for the therapeutic validation of the target results from the 0X1 /OX2 receptor antagonist ACT-078573 (20) [57], SB-649868 has also been announced to be in phase II clinical development, but neither the structural formula nor the results have been reported to date [58,59]. Moreover, insomnia treatments based on orexin modulation may be addressed by not only receptor antagonism but by inhibition of pathways related to the genesis of the bioactive peptides Orexin A or B, e.g. inhibition of Orexin-converting enzyme [60]. 

ACT-078573 (20) is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, 0X1 and 0X2 [61]. In animal models, the administration of 20 resulted in a dose-dependent decrease in alertness and increased non-REM and REM sleep. The compound, administered at oral doses ranging from 10 to 300 mg/kg, dose-dependently decreased alertness in rats and exhibited increased duration of REM and non-REM sleep, indicating no intrusive REM sleep that is characteristic of narcolepsy. In dogs, treatment with 20 (10-100 mg/kg p.o.) resulted in dose-dependent reductions in mobility and also induced signs of clinical somnolence. 

Clinical results with 20 have been recently reported from a phase I study that enrolled 70 healthy male human subjects. In this study, morning administration of the drug (200 mg and above) reduced alertness and latency to sleep stage 2 and increased time spent in sleep stage 2 with an overall improvement of sleep efficiency and total sleep time. These effects disappeared 6.5 h after drug administration [57], 

Currently the safety and efficacy of 20 is being evaluated in a Phase II study. The program is focused on the evaluation of the sleep induction and maintenance in insomnia patients but also will attempt to demonstrate orexin antagonists effects on improved sleep and side effect profiles compared to current GABAa receptor modulators. 

Quinolinyl compounds were first reported by Chan et al. as potent orexin receptor antagonists with excellent selectivity for OX1, good brain permeability and in vivo activity following i.p. dosing [62,63]. In fact, compounds SB-334867 (21), SB-408124 (22) and SB-410220 (23) displayed high affinity for the OX1 receptor in both whole cell (Ki — 99, 57 and 19nM, respectively) and membrane formats (X = 38, 27 and 4.5 nM, respectively). Meanwhile, native orexin peptides A and B display affinities for the OX1 receptor with K values of 318 and 1516 nM, respectively. In addition, calcium mobilization studies showed that all three are functional antagonists of the OX1 receptor, with potencies in line with their affinities, and with 50-fold 

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Tannenbaum PL, Stevens J, Binns J, Savitz AT, Garson SL, Fox SV, Coleman P, Kuduk SD, Gotter AL, Marino M, Tye SJ, Uslaner JM, Winrow CJ, Renger JJ (2014). Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs. Front Behav Neurosci 8 182. 

In a paper published electronically on June 24, 2016, Murphy and colleagues (Murphy et al. 2016) reported the use of concentration response (CR) modeling applied to data from two multiple ascending dose studies to examine the potential of lemborexant, a novel dual orexin receptor antagonist being developed to treat insomnia, to canse QT prolongation. The authors concluded as follows ... 

Proline bis-amides as potent dual orexin receptor antagonists with in vivo efficacy... 

I.Dingemanse, J. Dorffner, G. Hajak, G. Benes, H. Danker-Hopfe, H. Polo, O. Saletu, B. Barbanoj, M. J. Pillar, G. Penzel, T. Chiossi, E. Hoever, P. Proof-of-concept study in primary insomnia patients with almorexant (ACT-078573), a dual orexin receptor antagonist, World Sleep Congress Poster Presentation, Cairns, Australia, September 3-6, 2007. 

Almorexant is a first-in-class orexin receptor antagonist that was undergoing Phase III clinical trials for insomnia until 2011. The tetrahydroisoquinoline derivative was originally discovered from a series of Ugi/Pictet-Spengler reaction products. Originally developed by Actelion, from 2007 Almorexant was being reported as a potential... 

Bergman JM, Breslin MJ, Coleman PJ, Cox CD, Mercer SP, Roecker AJ (2008) Substituted diazepan orexin receptor antagonists. US2008/132490 (Al)... 

Suvorexant (brain penetrant dual orexin receptor antagonist for treatment of insomnia) [34]... 

Synthesis of Orexin Receptor Antagonist Suvorexant (MK-4305) Suvorexant (MK-4305) 93 is a potent and selective dual orexin receptor antagonist for... 

Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, Garson SL, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ. Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J. Neurogenet. 2011 25(l-2) 52-61. 

Baxter CA, Cleator E, Brands KMJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ. The first large-scale synthesis of MK-4305 a dual orexin receptor antagonist for the treatment of sleep disorder. Org. Process Res. Dev. 2011 15(2) 367-375. 

Girardin et al. (2013) reported the first kilogram-scale synthesis of MK-6096, which is an orexin receptor antagonist in clinical trials for the treatment of insomnia. 

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