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ID: ALA3098111
Journal: Bioorg Med Chem Lett
Title: Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs).
Authors: Mercer SP, Roecker AJ, Garson S, Reiss DR, Meacham Harrell C, Murphy KL, Bruno JG, Bednar RA, Lemaire W, Cui D, Cabalu TD, Tang C, Prueksaritanont T, Hartman GD, Young SD, Winrow CJ, Renger JJ, Coleman PJ.
Abstract: The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
CiteXplore: 24215892