Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors

Taiji Goto; Akiko Shiina; Toshiharu Yoshino; Kiyoshi Mizukami; Kazuki Hirahara; Osamu Suzuki; Yoshitaka Sogawa; Tomoko Takahashi; Tsuyoshi Mikkaichi; Naoki Nakao; Mizuki Takahashi; Masashi Hasegawa; Shigeki Sasaki

doi:10.1016/j.bmcl.2013.03.104

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors

Taiji Goto, Akiko Shiina, Toshiharu Yoshino, Kiyoshi Mizukami, Kazuki Hirahara, Osamu Suzuki, Yoshitaka Sogawa, Tomoko Takahashi, Tsuyoshi Mikkaichi, Naoki Nakao, Mizuki Takahashi, Masashi Hasegawa, Shigeki Sasaki

Chemo-Pharmaceutical Sciences

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

31 Citations (Scopus)

Abstract

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC ₅₀ = 150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC₅₀ = 25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC₅₀ = 7.5 nM) and TNF-α production in mouse splenocytes (IC₅₀ = 9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID₅₀ = 18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.

Original language	English
Pages (from-to)	3325-3328
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2013.03.104
Publication status	Published - Jun 1 2013

All Science Journal Classification (ASJC) codes

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

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Goto, T., Shiina, A., Yoshino, T., Mizukami, K., Hirahara, K., Suzuki, O., Sogawa, Y., Takahashi, T., Mikkaichi, T., Nakao, N., Takahashi, M., Hasegawa, M., & Sasaki, S. (2013). Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorganic and Medicinal Chemistry Letters, 23(11), 3325-3328. https://doi.org/10.1016/j.bmcl.2013.03.104

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. / Goto, Taiji; Shiina, Akiko; Yoshino, Toshiharu; Mizukami, Kiyoshi; Hirahara, Kazuki; Suzuki, Osamu; Sogawa, Yoshitaka; Takahashi, Tomoko; Mikkaichi, Tsuyoshi; Nakao, Naoki; Takahashi, Mizuki; Hasegawa, Masashi; Sasaki, Shigeki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 11, 01.06.2013, p. 3325-3328.

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

Goto, T, Shiina, A, Yoshino, T, Mizukami, K, Hirahara, K, Suzuki, O, Sogawa, Y, Takahashi, T, Mikkaichi, T, Nakao, N, Takahashi, M, Hasegawa, M & Sasaki, S 2013, 'Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 11, pp. 3325-3328. https://doi.org/10.1016/j.bmcl.2013.03.104

Goto, Taiji ; Shiina, Akiko ; Yoshino, Toshiharu ; Mizukami, Kiyoshi ; Hirahara, Kazuki ; Suzuki, Osamu ; Sogawa, Yoshitaka ; Takahashi, Tomoko ; Mikkaichi, Tsuyoshi ; Nakao, Naoki ; Takahashi, Mizuki ; Hasegawa, Masashi ; Sasaki, Shigeki. / Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 11. pp. 3325-3328.

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abstract = "2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC 50 = 150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50 = 25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50 = 7.5 nM) and TNF-α production in mouse splenocytes (IC50 = 9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50 = 18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.",

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