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Bioorg Med Chem Lett. 2016 Dec 1;26(23):5809-5814. doi: 10.1016/j.bmcl.2016.10.019. Epub 2016 Oct 14.

Discovery of highly potent and selective orexin 1 receptor antagonists (1-SORAs) suitable for in vivo interrogation of orexin 1 receptor pharmacology.

Author information

1
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
2
In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
3
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
4
Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.

Abstract

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.

KEYWORDS:

Dual orexin receptor antagonist (DORA); Filorexant; Orexin-1; Selective orexin receptor antagonist (SORA); Suvorexant

PMID:
27818110
DOI:
10.1016/j.bmcl.2016.10.019
[Indexed for MEDLINE]

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