【文章名】Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
作者
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 DONAHUI; HARTMAN GEORGE D; YOUNG STEVEN D; KOBLAN KEN S; WINROW CHRISTOPHER J; RENGER JOHN J; COLEMAN PAUL J
[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 to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquina-zoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
