Phase 2 clinical data with daridorexant support the lack of tolerance development to chronic treatment; efficacy of daridorexant was maintained up to 1 month in patients with insomnia, with no signals suggestive of withdrawal syndrome or rebound insomnia following cessation of daridorexant Dauvilliers et al.
This compound was discovered through an intensive drug discovery program on orexin receptor antagonists Boss et al.
The goal was to identify a potent, dual, and brain-penetrant orexin receptor antagonist with fast onset and a duration of action, long enough for covering the night, but short enough to avoid residual activity the following morning, at optimal efficacious doses.
In agreement with the nonclinical results and its appropriate pharmacokinetic profile Muehlan et al.
In the Zzz zone: the effects of Z-drugs on human performance and driving.
Rats are nocturnal animals as illustrated by the wakefulness a and sleep b profile over 24 h, depicted in 1 h bins; wakefulness is higher during the 12-h dark phase gray rectangle.
Almorexant is also known to exert antidepressant-like effects in mice Nollet et al.
In support of the clinical picture, in animals, zopiclone, zaleplon, and zolpidem have shown reinforcing effects, as well as withdrawal symptoms upon discontinuation after chronic use, indicative of abuse and dependence potential for humans Ator ; Ator et al.