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J Med Chem. 2015 Oct 22;58(20):7931-7. doi: 10.1021/acs.jmedchem.5b00988. Epub 2015 Aug 26.

Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists.

Author information

1
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
2
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
3
School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
4
Department of Molecular Genetics, University of Texas Southwestern Medical Center , Dallas, Texas 75390-8584, United States.

Abstract

Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 μM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4'-methoxy-N,N-dimethyl-3'-[N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl)sulfamoyl]-(1,1'-biphenyl)-3-carboxamide 26.

PMID:
26267383
DOI:
10.1021/acs.jmedchem.5b00988
[Indexed for MEDLINE]

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