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

doi:10.1016/j.bmc.2009.05.069

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
巻	17
号	16
DOI	https://doi.org/10.1016/j.bmc.2009.05.069
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

文献へのアクセス

10.1016/j.bmc.2009.05.069

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引用スタイル

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, 17(16), 6106-6122. https://doi.org/10.1016/j.bmc.2009.05.069

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.

研究成果: Article › 査読

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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