Discovery of highly potent and selective orexin 1 receptor antagonists (1-SORAs) suitable for in vivo interrogation of orexin 1 receptor pharmacology.
While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Craig A
CA
Stump
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Andrew J
AJ
Cooke
In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
Joseph
J
Bruno
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
Tamara D
TD
Cabalu
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
Anthony L
AL
Gotter
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
C Meacham
CM
Harell
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Scott D
SD
Kuduk
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
Terrence P
TP
McDonald
In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
Julie
J
O'Brien
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
John J
JJ
Renger
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Peter D
PD
Williams
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
Christopher J
CJ
Winrow
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Paul J
PJ
Coleman
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D000068796:Orexin Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D055647:Rats, Transgenic; D013329:Structure-Activity Relationship
D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010880:Piperidines
Dual orexin receptor antagonist (DORA); Filorexant; Orexin-1; Selective orexin receptor antagonist (SORA); Suvorexant