Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor

Makoto Ando, Nagaaki Sato, Tsuyoshi Nagase, Keita Nagai, Shiho Ishikawa, Hirobumi Takahashi, Norikazu Ohtake, Junko Ito, Mioko Hirayama, Yuko Mitobe, Hisashi Iwaasa, Akira Gomori, Hiroko Matsushita, Kiyoshi Tadano, Naoko Fujino, Sachiko Tanaka, Tomoyuki Ohe, Akane Ishihara, Akio Kanatani, Takehiro Fukami

研究成果: Article査読

16 被引用数 (Scopus)

抄録

A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.

本文言語English
ページ(範囲)6106-6122
ページ数17
ジャーナルBioorganic and Medicinal Chemistry
17
16
DOI
出版ステータスPublished - 2009 8 15
外部発表はい

ASJC Scopus subject areas

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

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