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Discovery of 5′′‐Chloro‐ N ‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia
Author(s) -
Roecker Anthony J.,
Mercer Swati P.,
Schreier John D.,
Cox Christopher D.,
Fraley Mark E.,
Steen Justin T.,
Lemaire Wei,
Bruno Joseph G.,
Harrell C. Meacham,
Garson Susan L.,
Gotter Anthony L.,
Fox Steven V.,
Stevens Joanne,
Tannenbaum Pamela L.,
Prueksaritat Thomayant,
Cabalu Tamara D.,
Cui Donghui,
Stellabott Joyce,
Hartman George D.,
Young Steven D.,
Winrow Christopher J.,
Renger John J.,
Coleman Paul J.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300447
Subject(s) - antagonist , pharmacology , orexin receptor , chemistry , orexin , antagonism , receptor , in vivo , stereochemistry , medicine , biology , biochemistry , neuropeptide , microbiology and biotechnology
The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 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 endogenous peptides at both the orexin 1 and orexin 2 receptors (OX 1 R and OX 2 R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX 1 R or OX 2 R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐ N ‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models.