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

被引：28

作者：

Goto, Taiji ^{[1
,4
]}

Shiina, Akiko ^{[2
]}

Murata, Takeshi ^{[1
]}

Tomii, Masato ^{[1
]}

Yamazaki, Takanori ^{[1
]}

Yoshida, Ken-ichi ^{[1
]}

Yoshino, Toshiharu ^{[1
]}

Suzuki, Osamu ^{[1
]}

Sogawa, Yoshitaka ^{[1
]}

Mizukami, Kiyoshi ^{[3
]}

Takagi, Nana ^{[1
]}

Yoshitomi, Tomomi ^{[1
]}

Etori, Maki ^{[1
]}

Tsuchida, Hiroshi ^{[1
]}

Mikkaichi, Tsuyoshi ^{[1
]}

Nakao, Naoki ^{[1
]}

Takahashi, Mizuki ^{[1
]}

Takahashi, Hisashi ^{[1
]}

Sasaki, Shigeki ^{[4
]}

机构：

[1] Daiichi Sankyo Co Ltd, R&D Div, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Qual & Safety Management Div, Chuo Ku, Tokyo 1038426, Japan

[3] Daiichi Sankyo Co Ltd, Corp Strategy Div, Chuo Ku, Tokyo 1038426, Japan

[4] Kyushu Univ, Grad Sch Pharmaceut Sci, Higashi Ku, Fukuoka 8128582, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 03期

关键词：

PDE4; PDE4B; PDE4D; Selective inhibitor; Full length; COPD; OBSTRUCTIVE PULMONARY-DISEASE; PHOSPHODIESTERASE; 4D; ROFLUMILAST; ENZYMES; ASTHMA; TARGET; COPD; MICE;

D O I：

10.1016/j.bmcl.2013.12.076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：893 / 899

页数：7

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