Discovery of the dual orexin receptor antagonist [(7 R)-4-(5-chloro-1, 3-benzoxazol-2-yl)-7-methyl-1, 4-diazepan-1-yl][5-methyl-2-(2 H-1, 2, 3-triazol-2-yl) phenyl] …

…, MJ Breslin, DB Whitman, JD Schreier…

文献索引：Cox, Christopher D.; Breslin, Michael J.; Whitman, David B.; Schreier, John D.; McGaughey, Georgia B.; Bogusky, Michael J.; Roecker, Anthony J.; Mercer, Swati P.; Bednar, Rodney A.; Lemaire, Wei; Bruno, Joseph G.; Reiss, Duane R.; Harrell, C. Meacham; Murphy, Kathy L.; Garson, Susan L.; Doran, Scott M.; Prueksaritanont, Thomayant; Anderson, Wayne B.; Tang, Cuyue; Roller, Shane; Cabalu, Tamara D.; Cui, Donghui; Hartman, George D.; Young, Steven D.; Koblan, Ken S.; Winrow, Christopher J.; Renger, John J.; Coleman, Paul J. Journal of Medicinal Chemistry, 2010 , vol. 53, # 14 p. 5320 - 5332

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被引用次数: 166

摘要

Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led ...