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

Takashi Nagahara, Tsuyoshi Saitoh, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Daisuke Kuroda, Hiroaki Gouda, Hidetoshi Kumagai, Hideaki Fujii, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7931-7937
Number of pages7
JournalJournal of Medicinal Chemistry
Volume58
Issue number20
DOIs
StatePublished - Aug 12 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Nagahara, T., Saitoh, T., Kutsumura, N., Irukayama-Tomobe, Y., Ogawa, Y., Kuroda, D., Gouda, H., Kumagai, H., Fujii, H., Yanagisawa, M., & Nagase, H. (2015). Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. Journal of Medicinal Chemistry, 58(20), 7931-7937. https://doi.org/10.1021/acs.jmedchem.5b00988