title: Almorexant, a dual orexin receptor antagonist for the treatment of insomnia.
abstract: Almorexant (ACT-078573) is an orally active dual orexin receptor antagonist that is being developed by Actelion Ltd, in collaboration with GlaxoSmithKline plc, for the treatment of primary insomnia. Almorexant is a first-in-class compound that targets the orexin system, which plays a key role in wake promotion and stabilization, in addition to having other regulatory functions. Decreasing orexin activity was hypothesized to have a sleep-promoting effect. Preclinical studies and phase I clinical trials have demonstrated that almorexant decreases alertness and increases sleep in healthy rats, dogs and humans when administered during the active phase of the circadian cycle, at peak endogenous orexin tone. No significant toxicological or safety concerns have been identified in studies in animals and humans, including no evidence of cataplexy, a sudden postural muscle tone weakening that is triggered by emotional stimuli and is considered unique to narcolepsy. The reported efficacy and safety data for almorexant support the continued development of the compound. At the time of publication, phase III clinical trials were underway, but no results had been reported; Actelion and GlaxoSmithKline were also investigating almorexant for other orexin-related neurological disorders. The use of an orexin receptor antagonist for the treatment of sleep disorders appears to be an approach that may provide unique benefits.
authors.affiliation: Johns Hopkins Bayview Medical Center, Department of Psychiatry, 4940 Eastern Avenue, Box 151, Baltimore, MD 21224, USA. neubauer@jhmi.edu
authors.forename: David N
authors.initials: DN
authors.lastname: Neubauer
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D000075202:Contraindications; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D064446:Orexin Receptors; D010330:Patents as Topic; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C519150:almorexant