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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• 作者：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
• 关键词：PDE4 ; PDE4B ; PDE4D ; Selective inhibitor ; Full length ; COPD
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 February, 2014
• 年：2014
• 卷：24
• 期：3
• 页码：893-899
• 全文大小：2848 K

文摘

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.