title: Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders.
abstract: The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
authors.affiliation: GlaxoSmithKline Medicine Research Centre, Via A. Fleming, 4, 37135 Verona, Italy. romano.difabio@aptuit.com
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pellacani
authors.forename: Stefania
authors.initials: S
authors.lastname: Faedo
authors.forename: Adelheid
authors.initials: A
authors.lastname: Roth
authors.forename: Laura
authors.initials: L
authors.lastname: Piccoli
authors.forename: Philip
authors.initials: P
authors.lastname: Gerrard
authors.forename: Rod A
authors.initials: RA
authors.lastname: Porter
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Kevin
authors.initials: K
authors.lastname: Thewlis
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Luigi
authors.initials: L
authors.lastname: Stasi
authors.forename: Simone
authors.initials: S
authors.lastname: Spada
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: David
authors.initials: D
authors.lastname: Nash
authors.forename: Clive
authors.initials: C
authors.lastname: Branch
authors.forename: Leanda
authors.initials: L
authors.lastname: Kindon
authors.forename: Mario
authors.initials: M
authors.lastname: Massagrande
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poffe
authors.forename: Simone
authors.initials: S
authors.lastname: Braggio
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Chiarparin
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Emiliangelo
authors.initials: E
authors.lastname: Ratti
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D064446:Orexin Receptors; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D064446:Orexin Receptors; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C032727:piperidine