Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect

Nagaaki Sato, Makoto Ando, Shiho Ishikawa, Makoto Jitsuoka, Keita Nagai, Hirobumi Takahashi, Aya Sakuraba, Hiroyasu Tsuge, Hidefumi Kitazawa, Hisashi Iwaasa, Satoshi Mashiko, Akira Gomori, Ryuichi Moriya, Naoko Fujino, Tomoyuki Ohe, Akane Ishihara, Akio Kanatani, Takehiro Fukami

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp34NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

Original languageEnglish
Pages (from-to)3385-3396
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number10
DOIs
Publication statusPublished - 2009 May 28
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Sato, N., Ando, M., Ishikawa, S., Jitsuoka, M., Nagai, K., Takahashi, H., Sakuraba, A., Tsuge, H., Kitazawa, H., Iwaasa, H., Mashiko, S., Gomori, A., Moriya, R., Fujino, N., Ohe, T., Ishihara, A., Kanatani, A., & Fukami, T. (2009). Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect. Journal of Medicinal Chemistry, 52(10), 3385-3396. https://doi.org/10.1021/jm900110t