title: Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist.
abstract: The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.
authors.affiliation: Drug Discovery and Preclinical Research & Development, Actelion Pharmaceuticals Ltd. Gewerbestrasse 16, 4123 Allschwil/BL (Switzerland). christoph.boss@actelion.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
authors.forename: Catherine
authors.initials: C
authors.lastname: Roch-Brisbare
authors.forename: Michel A
authors.initials: MA
authors.lastname: Steiner
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dietrich
authors.forename: Francois
authors.initials: F
authors.lastname: Jenck
authors.forename: Markus
authors.initials: M
authors.lastname: von Raumer
authors.forename: Thierry
authors.initials: T
authors.lastname: Sifferlen
authors.forename: Christine
authors.initials: C
authors.lastname: Brotschi
authors.forename: Bibia
authors.initials: B
authors.lastname: Heidmann
authors.forename: Jodi T
authors.initials: JT
authors.lastname: Williams
authors.forename: Hamed
authors.initials: H
authors.lastname: Aissaoui
authors.forename: Romain
authors.initials: R
authors.lastname: Siegrist
authors.forename: John
authors.initials: J
authors.lastname: Gatfield
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D006207:Half-Life; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D018377:Neurotransmitter Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: C000596436:ACT-462206; D018377:Neurotransmitter Agents; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011759:Pyrrolidines; D013449:Sulfonamides; D011392:Proline
keywords: insomnia; neurotransmitters; orexin receptor antagonists; peptides; stress-related disorders