Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist

Yuji Haga; Toshihiro Sakamoto; Takunobu Shibata; Katsumasa Nonoshita; Makoto Ishikawa; Takuya Suga; Hirobumi Takahashi; Toshiyuki Takahashi; Hidekazu Takahashi; Makoto Ando; Takashi Murai; Akira Gomori; Zenjun Oda; Hidefumi Kitazawa; Yuko Mitobe; Maki Kanesaka; Tomoyuki Ohe; Hisashi Iwaasa; Yasuyuki Ishii; Akane Ishihara; Akio Kanatani; Takehiro Fukami

doi:10.1016/j.bmc.2009.08.019

Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist

Yuji Haga, Toshihiro Sakamoto, Takunobu Shibata, Katsumasa Nonoshita, Makoto Ishikawa, Takuya Suga, Hirobumi Takahashi, Toshiyuki Takahashi, Hidekazu Takahashi, Makoto Ando, Takashi Murai, Akira Gomori, Zenjun Oda, Hidefumi Kitazawa, Yuko Mitobe, Maki Kanesaka, Tomoyuki Ohe, Hisashi Iwaasa, Yasuyuki Ishii, Akane IshiharaAkio Kanatani, Takehiro Fukami

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

15 Citations (Scopus)

Abstract

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

Original language	English
Pages (from-to)	6971-6982
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2009.08.019
Publication status	Published - 2009 Oct 1
Externally published	Yes

Keywords

Antagonist
NPY
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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10.1016/j.bmc.2009.08.019

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Haga, Y., Sakamoto, T., Shibata, T., Nonoshita, K., Ishikawa, M., Suga, T., Takahashi, H., Takahashi, T., Takahashi, H., Ando, M., Murai, T., Gomori, A., Oda, Z., Kitazawa, H., Mitobe, Y., Kanesaka, M., Ohe, T., Iwaasa, H., Ishii, Y., ... Fukami, T. (2009). Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist. Bioorganic and Medicinal Chemistry, 17(19), 6971-6982. https://doi.org/10.1016/j.bmc.2009.08.019

Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist. / Haga, Yuji; Sakamoto, Toshihiro; Shibata, Takunobu et al.
In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 19, 01.10.2009, p. 6971-6982.

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

Haga, Y, Sakamoto, T, Shibata, T, Nonoshita, K, Ishikawa, M, Suga, T, Takahashi, H, Takahashi, T, Takahashi, H, Ando, M, Murai, T, Gomori, A, Oda, Z, Kitazawa, H, Mitobe, Y, Kanesaka, M, Ohe, T, Iwaasa, H, Ishii, Y, Ishihara, A, Kanatani, A & Fukami, T 2009, 'Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist', Bioorganic and Medicinal Chemistry, vol. 17, no. 19, pp. 6971-6982. https://doi.org/10.1016/j.bmc.2009.08.019

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abstract = "A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.",

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doi = "10.1016/j.bmc.2009.08.019",

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AU - Haga, Yuji

AU - Sakamoto, Toshihiro

AU - Shibata, Takunobu

AU - Nonoshita, Katsumasa

AU - Ishikawa, Makoto

AU - Suga, Takuya

AU - Takahashi, Hirobumi

AU - Takahashi, Toshiyuki

AU - Takahashi, Hidekazu

AU - Ando, Makoto

AU - Murai, Takashi

AU - Gomori, Akira

AU - Oda, Zenjun

AU - Kitazawa, Hidefumi

AU - Mitobe, Yuko

AU - Kanesaka, Maki

AU - Ohe, Tomoyuki

AU - Iwaasa, Hisashi

AU - Ishii, Yasuyuki

AU - Ishihara, Akane

AU - Kanatani, Akio

AU - Fukami, Takehiro

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AB - A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

KW - Antagonist

KW - NPY

KW - Neuropeptide Y

KW - Y5 receptor

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Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist

Abstract

Keywords

ASJC Scopus subject areas

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