Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists

https://doi.org/10.1016/j.bmcl.2011.08.093Get rights and content

Abstract

During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σp and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.

Graphical abstract

During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σp and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.

  1. Download : Download full-size image

References and notes (13)

  • T. Sakurai et al.

    Cell

    (1998)
  • J.M. Bergman et al.

    Bioorg. Med. Chem. Lett.

    (2008)
  • M.G. Lee et al.

    J. Neurosci.

    (2005)
    I.V. Estabrooke et al.

    J. Neurosci.

    (2001)
  • P.J. Coleman et al.

    Expert Opin. Ther. Patents

    (2010)
    J. Gatfield et al.

    ChemMedChem

    (2010)
    C. Brisbare-Roch et al.

    Nat. Med.

    (2007)
    (d)Coleman, P. J.; Cox, C. D.; Breslin, M. J.; Schreier, J. D.; Roecker, A. J.; Whitman, D. B.; Mercer, S. P.; Bergman,...C.D. Cox et al.

    J. Med. Chem.

    (2010)
    C.J. Winrow et al.

    J. Neurogenet.

    (2011)
There are more references available in the full text version of this article.

Cited by (28)

  • 1,4-Oxazepines and 1,4-Thiazepines

    2021, Comprehensive Heterocyclic Chemistry IV
  • TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice

    2019, Pharmacology Biochemistry and Behavior
    Citation Excerpt :

    TAK-925 and compound 1 m [(3R,5S)-4-(4-Chlorobenzoyl)-7-(difluoromethoxy)-3,5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine] were synthesized by Takeda Pharmaceutical Company Limited. Compound 1 m was reported to be a potent and selective OX2R antagonist (50% inhibitory concentration (IC50) = 27 nM with 100-fold selectivity against OX1R) (Fujimoto et al., 2011). [ 3H]T-516 (777 GBq/mL) was synthesized by BioBridge K.K. (Tokyo, Japan).

  • Synthesis, anti-cancer evaluation of benzenesulfonamide derivatives as potent tubulin-targeting agents

    2016, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Our precious work revealed that cyclopropyl-oxazole moiety was crucial for cytotoxicity. Moreover, benzodiazepine, benzoxazepine and benzothiazepine skeleton as crucial pharmacophore cores have attracted much attention in the past years owning to its broad spectrum of biological activities especially anticancer [13–17], anticonvulsant [18], CNS activities [19,20] and others [21]. To continue our earlier work [12], we designed the ring expansion series (3, Fig. 1) of the lead compound 1, expecting an improvement in drug potency and water solubility.

  • Synthesis of new benzo[f]imidazo[1,2-d][1,4]oxazepines: AgNO<inf>3</inf>-mediated intramolecular hydroamination

    2015, Tetrahedron Letters
    Citation Excerpt :

    Hence, the development of new and operationally simple synthetic approaches is still in demand in the field of heterocyclic compounds. Intramolecular and intermolecular hydroamination reactions, the addition of an amine to an unsaturated carbon–carbon, are useful reactions for the direct formation of the C–N bond in N-heterocycle synthesis.12–14 The hydroamination reaction is typically catalyzed by metals,12–14 as the repulsion between a nitrogen lone pair and the olefin/alkyne π electrons must be overcome in these reactions.

  • Design, synthesis, and structure-activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists

    2014, Bioorganic and Medicinal Chemistry
    Citation Excerpt :

    Therefore, further studies are needed to characterize dual orexin antagonists and selective orexin antagonists for potential use as sleep drugs. Given the therapeutic potential of the orexin system, orexin receptor antagonists have been a significant focus of drug discovery research, primarily for treating insomnia.19–24 The best studied dual orexin antagonist to date is almorexant (1),25 which was developed by Actelion/GlaxoSmithKline for the treatment of insomnia but discontinued at the phase III clinical trial stage.

View all citing articles on Scopus
View full text