Compound 12 (LY-156735/PD-6735) is a melatonin MT1 and MT2 agonist currently undergoing phase II trials for the improvement of sleep onset latency in patients with primary insomnia. In 2001, the compound was assigned orphan drug status for the treatment of circadian rhythm sleep disorders in blind patients with no light perception. The compound has been shown to be safe and well tolerated. In addition, it dose-dependently reduces objective polysomnographic sleep parameters without producing any morning-after psychomotor impairment, as well as reducing the subjective time to fall asleep in patients with moderate to severe primary insomnia [32-37]. 12 demonstrated chronobiotic efficacy in healthy volunteers undergoing simulated shift lag  and showed adequate pharmacokinetics, pharmacodynamics and safety at doses of 20-40 mg in healthy volunteers .
VEC-162 is a dual MT1/MT2 melatonin agonist in phase II trials (no structure disclosed). A study in 39 subjects revealed that the compound (10-100 mg p.o.) dose-dependently, and on initial administration, advanced phases of melatonin circadian rhythm by up to 5 h. Sleep analysis also confirmed that these effects are associated with improved overall sleep efficacy, reduced sleep latency and attenuated rapid-eye-movement (REM) sleep. VEC-162 may therefore be beneficial for the management of sleep-wake disorders in subjects who rapidly shift their circadian phase . The announced phase III study aimed at evaluating the safety and efficacy of VEC-162 compared to placebo in healthy subjects with induced transient insomnia has recently ended the patient recruitment phase .
Agomelatine (13) represents an outsider within this group, because it is not in development for insomnia but for depression and anxiety. Although it is a MT1/MT2 receptor agonist in the picomolar range, it also displayed potent affinity for the 5HT2c receptor (IC50 = 270 nM). This compound was extensively reviewed in 2004 [29,42], and, since then, new phase III trials for major depressive disorder were completed. However, the European Medicines Agency (EMEA) refused authorization in July 2006 due to concerns about its effectiveness .
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