The field of small molecule orexin antagonist research has evolved rapidly in the last fifteen years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of peptides at both the orexin-1 and orexin-2 receptors (OX1R and OX2R), termed dual orexin receptor antagonists (DORAs). Full characterization of the pharmacology associated with antagonism of either OX1R or OX2R alone has been hampered by a dearth of suitable subtype selective, orally biovailable ligands. Herein we report the optimization of a selective orexin 2 antagonist (2-SORA) HTS screening lead to afford a potent, orally bioavailable 2-SORA ligand. During the course of these efforts several challenging medicinal chemistry issues were identified and overcome including reversible CYP inhibition, physical properties, P-glycoprotein susceptibility and bioactivation. This presentation will highlight the structural modifications the team utilized to drive compound design as well as in vivo characterization of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064) in animal sleep models.

Discovery of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064): A Potent, orally bioavailable, selective orexin 2 receptor antagonist that effectively promotes sleep in preclinical animal models

247th National Meeting (2014)

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