Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders

作者：Di Fabio Romano^*; Pellacani Annalisa; Faedo Stefania; Roth Adelheid; Piccoli Laura; Gerrard Philip; Porter Rod A; Johnson Christopher N; Thewlis Kevin; Donati Daniele; Stasi Luigi; Spada Simone; Stemp Geoffrey; Nash David; Branch Clive; Kindon Leanda; Massagrande Mario; Poffe Alessandro; Braggio Simone; Chiarparin Elisabetta; Marchioro Carla; Ratti Emiliangelo; Corsi Mauro

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(18): 5562-5567.

DOI：10.1016/j.bmcl.2011.06.086

• Orexin receptor antagonist
• G-Protein coupled receptor (GPCR)
• Central nervous system (CNS)
• Sleep disorders
• Hypnotic agent
• Conformational analysis
• Structure-activity relationship (SAR)

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.

• 出版日期2011-9-15