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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6106-6122
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number16
DOIs
Publication statusPublished - 2009 Aug 15
Externally publishedYes

Fingerprint

Neuropeptide Y Receptors
Pyridones
Imidazolines
Neuropeptide Y
Eating
Oral Administration
Rats
Brain
Dogs
Derivatives
Plasmas
neuropeptide Y5 receptor
2-hydroxypyridine
2-imidazoline
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

Keywords

  • Anti-obesity
  • Imidazoline class
  • Neuropeptide Y Y5 receptor
  • Y5 antagonist

ASJC Scopus subject areas

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

Cite this

Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor. / Ando, Makoto; Sato, Nagaaki; Nagase, Tsuyoshi; Nagai, Keita; Ishikawa, Shiho; Takahashi, Hirobumi; Ohtake, Norikazu; Ito, Junko; Hirayama, Mioko; Mitobe, Yuko; Iwaasa, Hisashi; Gomori, Akira; Matsushita, Hiroko; Tadano, Kiyoshi; Fujino, Naoko; Tanaka, Sachiko; Ohe, Tomoyuki; Ishihara, Akane; Kanatani, Akio; Fukami, Takehiro.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 16, 15.08.2009, p. 6106-6122.

Research output: Contribution to journalArticle

Ando, M, Sato, N, Nagase, T, Nagai, K, Ishikawa, S, Takahashi, H, Ohtake, N, Ito, J, Hirayama, M, Mitobe, Y, Iwaasa, H, Gomori, A, Matsushita, H, Tadano, K, Fujino, N, Tanaka, S, Ohe, T, Ishihara, A, Kanatani, A & Fukami, T 2009, 'Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor', Bioorganic and Medicinal Chemistry, vol. 17, no. 16, pp. 6106-6122. https://doi.org/10.1016/j.bmc.2009.05.069
Ando, Makoto ; Sato, Nagaaki ; Nagase, Tsuyoshi ; Nagai, Keita ; Ishikawa, Shiho ; Takahashi, Hirobumi ; Ohtake, Norikazu ; Ito, Junko ; Hirayama, Mioko ; Mitobe, Yuko ; Iwaasa, Hisashi ; Gomori, Akira ; Matsushita, Hiroko ; Tadano, Kiyoshi ; Fujino, Naoko ; Tanaka, Sachiko ; Ohe, Tomoyuki ; Ishihara, Akane ; Kanatani, Akio ; Fukami, Takehiro. / Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 16. pp. 6106-6122.
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