鉴定5,5 - 二氧代 - 7,8 - 二氢 - 6H - 硫代吡喃并[3,2 - d]嘧啶衍生物为高选择性磷酸二酯酶4B（PDE4B）抑制剂。
Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors.
作者信息
Goto Taiji, Shiina Akiko, Murata Takeshi, Tomii Masato, Yamazaki Takanori, Yoshida Ken-ichi, Yoshino Toshiharu, Suzuki Osamu, Sogawa Yoshitaka, Mizukami Kiyoshi, Takagi Nana, Yoshitomi Tomomi, Etori Maki, Tsuchida Hiroshi, Mikkaichi Tsuyoshi, Nakao Naoki, Takahashi Mizuki, Takahashi Hisashi, Sasaki Shigeki
机构信息
R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Quality & Safety Management Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan.
出版信息
Bioorg Med Chem Lett. 2014 Feb 1;24(3):893-9. doi: 10.1016/j.bmcl.2013.12.076. Epub 2013 Dec 25.
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.
预计一种PDE4B亚型选择性抑制剂比非选择性PDE4抑制剂具有更宽的治疗窗口。在本信函中，使用人PDE4B2和PDE4D2全长酶对两个系列的7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶衍生物和5,5-二氧代-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶衍生物进行了PDE4B亚型选择性评估。为了提高它们对PDE4D的PDE4B选择性，我们优化了嘧啶环和侧链苯环上的取代基，得到了几种对PDE4B具有100倍以上选择性的衍生物。因此，我们确定2-(3-氯-4-甲氧基-苯基)-5,5-二氧代-7,8-二氢-6H-硫代吡喃并[3,2-d]嘧啶衍生物54为一种高选择性PDE4B抑制剂，其对hPDE4B具有强效抑制活性，IC50值为3.0 nM，对PDE4D的PDE4B选择性为433倍。
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