Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists

Yoshio Ogino; Norikazu Ohtake; Yoshikazu Nagae; Kenji Matsuda; Makoto Ishikawa; Minoru Moriya; Maki Kanesaka; Yuko Mitobe; Junko Ito; Tetsuya Kanno; Akane Ishihara; Hisashi Iwaasa; Tomoyuki Ohe; Akio Kanatani; Takehiro Fukami

doi:10.1016/j.bmcl.2008.08.021

Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists

Yoshio Ogino, Norikazu Ohtake, Yoshikazu Nagae, Kenji Matsuda, Makoto Ishikawa, Minoru Moriya, Maki Kanesaka, Yuko Mitobe, Junko Ito, Tetsuya Kanno, Akane Ishihara, Hisashi Iwaasa, Tomoyuki Ohe, Akio Kanatani, Takehiro Fukami

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

15 Citations (Scopus)

Abstract

Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC₅₀ = 3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC₅₀ = 5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists. Crown

Original language	English
Pages (from-to)	4997-5001
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2008.08.021
Publication status	Published - 2008 Sep 15
Externally published	Yes

Keywords

Antagonist
Anti-obesity
Benzimidazole
Neuropeptide Y
Y5 receptor

ASJC Scopus subject areas

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

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Ogino, Y., Ohtake, N., Nagae, Y., Matsuda, K., Ishikawa, M., Moriya, M., Kanesaka, M., Mitobe, Y., Ito, J., Kanno, T., Ishihara, A., Iwaasa, H., Ohe, T., Kanatani, A., & Fukami, T. (2008). Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 18(18), 4997-5001. https://doi.org/10.1016/j.bmcl.2008.08.021

Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists. / Ogino, Yoshio; Ohtake, Norikazu; Nagae, Yoshikazu; Matsuda, Kenji; Ishikawa, Makoto; Moriya, Minoru; Kanesaka, Maki; Mitobe, Yuko; Ito, Junko; Kanno, Tetsuya; Ishihara, Akane; Iwaasa, Hisashi; Ohe, Tomoyuki; Kanatani, Akio; Fukami, Takehiro.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 18, 15.09.2008, p. 4997-5001.

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

Ogino, Y, Ohtake, N, Nagae, Y, Matsuda, K, Ishikawa, M, Moriya, M, Kanesaka, M, Mitobe, Y, Ito, J, Kanno, T, Ishihara, A, Iwaasa, H, Ohe, T, Kanatani, A & Fukami, T 2008, 'Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 18, pp. 4997-5001. https://doi.org/10.1016/j.bmcl.2008.08.021

Ogino Y, Ohtake N, Nagae Y, Matsuda K, Ishikawa M, Moriya M et al. Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists. Bioorganic and Medicinal Chemistry Letters. 2008 Sep 15;18(18):4997-5001. https://doi.org/10.1016/j.bmcl.2008.08.021

Ogino, Yoshio ; Ohtake, Norikazu ; Nagae, Yoshikazu ; Matsuda, Kenji ; Ishikawa, Makoto ; Moriya, Minoru ; Kanesaka, Maki ; Mitobe, Yuko ; Ito, Junko ; Kanno, Tetsuya ; Ishihara, Akane ; Iwaasa, Hisashi ; Ohe, Tomoyuki ; Kanatani, Akio ; Fukami, Takehiro. / Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 18. pp. 4997-5001.

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abstract = "Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC50 = 3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC50 = 5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists. Crown",

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author = "Yoshio Ogino and Norikazu Ohtake and Yoshikazu Nagae and Kenji Matsuda and Makoto Ishikawa and Minoru Moriya and Maki Kanesaka and Yuko Mitobe and Junko Ito and Tetsuya Kanno and Akane Ishihara and Hisashi Iwaasa and Tomoyuki Ohe and Akio Kanatani and Takehiro Fukami",

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AU - Ohtake, Norikazu

AU - Nagae, Yoshikazu

AU - Matsuda, Kenji

AU - Ishikawa, Makoto

AU - Moriya, Minoru

AU - Kanesaka, Maki

AU - Mitobe, Yuko

AU - Ito, Junko

AU - Kanno, Tetsuya

AU - Ishihara, Akane

AU - Iwaasa, Hisashi

AU - Ohe, Tomoyuki

AU - Kanatani, Akio

AU - Fukami, Takehiro

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AB - Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC50 = 3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC50 = 5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists. Crown

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Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists

Abstract

Keywords

ASJC Scopus subject areas

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