title: 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.
abstract: 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 (OX1 R and OX2 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 OX1 R or OX2 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486 (USA). anthony_roecker@merck.com.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.forename: Swati P
authors.initials: SP
authors.lastname: Mercer
authors.forename: John D
authors.initials: JD
authors.lastname: Schreier
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Justin T
authors.initials: JT
authors.lastname: Steen
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Cabalu
authors.forename: Donghui
authors.initials: D
authors.lastname: Cui
authors.forename: Joyce
authors.initials: J
authors.lastname: Stellabott
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Young
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004285:Dogs; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068797:Orexins; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D011725:Pyridines
keywords: antagonists; insomnia; medicinal chemistry; neurotransmitters; orexin receptors