Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group

Tsuyoshi Saitoh, Kazunori Seki, Ryo Nakajima, Naoshi Yamamoto, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Masashi Yanagisawa, Hiroshi Nagase

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Abstract

The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

Original languageEnglish (US)
Article number126893
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number3
DOIs
StatePublished - Feb 1 2020

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Keywords

  • Nalfurafine
  • Orexin
  • Ring removal
  • Substituent effect
  • YNT-707

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Saitoh, T., Seki, K., Nakajima, R., Yamamoto, N., Kutsumura, N., Nagumo, Y., Irukayama-Tomobe, Y., Ogawa, Y., Ishikawa, Y., Yanagisawa, M., & Nagase, H. (2020). Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group. Bioorganic and Medicinal Chemistry Letters, 30(3), [126893]. https://doi.org/10.1016/j.bmcl.2019.126893