Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors

Taiji Goto; Akiko Shiina; Takeshi Murata; Masato Tomii; Takanori Yamazaki; Ken Ichi Yoshida; Toshiharu Yoshino; Osamu Suzuki; Yoshitaka Sogawa; Kiyoshi Mizukami; Nana Takagi; Tomomi Yoshitomi; Maki Etori; Hiroshi Tsuchida; Tsuyoshi Mikkaichi; Naoki Nakao; Mizuki Takahashi; Hisashi Takahashi; Shigeki Sasaki

doi:10.1016/j.bmcl.2013.12.076

Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors

Taiji Goto, Akiko Shiina, Takeshi Murata, Masato Tomii, Takanori Yamazaki, Ken Ichi Yoshida, Toshiharu Yoshino, Osamu Suzuki, Yoshitaka Sogawa, Kiyoshi Mizukami, Nana Takagi, Tomomi Yoshitomi, Maki Etori, Hiroshi Tsuchida, Tsuyoshi Mikkaichi, Naoki Nakao, Mizuki Takahashi, Hisashi Takahashi, Shigeki Sasaki

Chemo-Pharmaceutical Sciences

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

28 Citations (Scopus)

Abstract

A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8- dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3, 2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC₅₀ value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

Original language	English
Pages (from-to)	893-899
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2013.12.076
Publication status	Published - Feb 1 2014

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmcl.2013.12.076

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Goto, T., Shiina, A., Murata, T., Tomii, M., Yamazaki, T., Yoshida, K. I., Yoshino, T., Suzuki, O., Sogawa, Y., Mizukami, K., Takagi, N., Yoshitomi, T., Etori, M., Tsuchida, H., Mikkaichi, T., Nakao, N., Takahashi, M., Takahashi, H., & Sasaki, S. (2014). Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors. Bioorganic and Medicinal Chemistry Letters, 24(3), 893-899. https://doi.org/10.1016/j.bmcl.2013.12.076

Goto, T, Shiina, A, Murata, T, Tomii, M, Yamazaki, T, Yoshida, KI, Yoshino, T, Suzuki, O, Sogawa, Y, Mizukami, K, Takagi, N, Yoshitomi, T, Etori, M, Tsuchida, H, Mikkaichi, T, Nakao, N, Takahashi, M, Takahashi, H & Sasaki, S 2014, 'Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 3, pp. 893-899. https://doi.org/10.1016/j.bmcl.2013.12.076

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abstract = "A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8- dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3, 2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.",

author = "Taiji Goto and Akiko Shiina and Takeshi Murata and Masato Tomii and Takanori Yamazaki and Yoshida, {Ken Ichi} and Toshiharu Yoshino and Osamu Suzuki and Yoshitaka Sogawa and Kiyoshi Mizukami and Nana Takagi and Tomomi Yoshitomi and Maki Etori and Hiroshi Tsuchida and Tsuyoshi Mikkaichi and Naoki Nakao and Mizuki Takahashi and Hisashi Takahashi and Shigeki Sasaki",

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T1 - Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors

AU - Goto, Taiji

AU - Shiina, Akiko

AU - Murata, Takeshi

AU - Tomii, Masato

AU - Yamazaki, Takanori

AU - Yoshida, Ken Ichi

AU - Yoshino, Toshiharu

AU - Suzuki, Osamu

AU - Sogawa, Yoshitaka

AU - Mizukami, Kiyoshi

AU - Takagi, Nana

AU - Yoshitomi, Tomomi

AU - Etori, Maki

AU - Tsuchida, Hiroshi

AU - Mikkaichi, Tsuyoshi

AU - Nakao, Naoki

AU - Takahashi, Mizuki

AU - Takahashi, Hisashi

AU - Sasaki, Shigeki

PY - 2014/2/1

Y1 - 2014/2/1

N2 - A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8- dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3, 2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

AB - A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8- dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3, 2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

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Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors

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