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

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

  • J Med Chem. 2015 Oct 22;58(20):7931-7. doi: 10.1021/acs.jmedchem.5b00988.
Takashi Nagahara 1,  Tsuyoshi Saitoh 2,  Noriki Kutsumura 2,  Yoko Irukayama-Tomobe 2,  Yasuhiro Ogawa 2,  Daisuke Kuroda 3,  Hiroaki Gouda 3,  Hidetoshi Kumagai 2 4,  Hideaki Fujii 1,  Masashi Yanagisawa 2 4,  Hiroshi Nagase 2 1
Affiliations

Affiliations

  • 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.
PMID: 26267383 DOI: 10.1021/acs.jmedchem.5b00988
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.

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