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

Research output: Contribution to journal › Article › peer-review

19 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 language	English
Pages (from-to)	6106-6122
Number of pages	17
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	16
DOIs	https://doi.org/10.1016/j.bmc.2009.05.069
Publication status	Published - 2009 Aug 15
Externally published	Yes

Keywords

Anti-obesity
Imidazoline class
Neuropeptide Y Y5 receptor
Y5 antagonist

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2009.05.069

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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

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

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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.",

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AU - Ando, Makoto

AU - Sato, Nagaaki

AU - Nagase, Tsuyoshi

AU - Nagai, Keita

AU - Ishikawa, Shiho

AU - Takahashi, Hirobumi

AU - Ohtake, Norikazu

AU - Ito, Junko

AU - Hirayama, Mioko

AU - Mitobe, Yuko

AU - Iwaasa, Hisashi

AU - Gomori, Akira

AU - Matsushita, Hiroko

AU - Tadano, Kiyoshi

AU - Fujino, Naoko

AU - Tanaka, Sachiko

AU - Ohe, Tomoyuki

AU - Ishihara, Akane

AU - Kanatani, Akio

AU - Fukami, Takehiro

PY - 2009/8/15

Y1 - 2009/8/15

N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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