Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists

Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 mu M) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4'-methoxy-N,N-dimethy1-3'-[N-(3-{[2-(3-methylbenzamido) ethyl] amino}phenyl) sulfamoyl]-(1,1'-biphenyl)-3-carboxamide 26.