Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist

Yuji Haga, Toshihiro Sakamoto, Takunobu Shibata, Katsumasa Nonoshita, Makoto Ishikawa, Takuya Suga, Hirobumi Takahashi, Toshiyuki Takahashi, Hidekazu Takahashi, Makoto Ando, Takashi Murai, Akira Gomori, Zenjun Oda, Hidefumi Kitazawa, Yuko Mitobe, Maki Kanesaka, Tomoyuki Ohe, Hisashi Iwaasa, Yasuyuki Ishii, Akane IshiharaAkio Kanatani, Takehiro Fukami

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

Original languageEnglish
Pages (from-to)6971-6982
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number19
DOIs
Publication statusPublished - 2009 Oct 1
Externally publishedYes

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Keywords

  • Antagonist
  • NPY
  • Neuropeptide Y
  • Y5 receptor

ASJC Scopus subject areas

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

Cite this

Haga, Y., Sakamoto, T., Shibata, T., Nonoshita, K., Ishikawa, M., Suga, T., Takahashi, H., Takahashi, T., Takahashi, H., Ando, M., Murai, T., Gomori, A., Oda, Z., Kitazawa, H., Mitobe, Y., Kanesaka, M., Ohe, T., Iwaasa, H., Ishii, Y., ... Fukami, T. (2009). Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist. Bioorganic and Medicinal Chemistry, 17(19), 6971-6982. https://doi.org/10.1016/j.bmc.2009.08.019