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

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28 Citations (Scopus)


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 languageEnglish
Pages (from-to)893-899
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Issue number3
Publication statusPublished - 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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