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

共 50 条

[21] Synthesis of new condensed derivatives of pyrano[4,3-b]thieno[3,2-e]pyridine and pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
V. V. Dabaeva
M. R. Bagdasaryan
A. S. Noravyan
Chemistry of Heterocyclic Compounds, 2011, 47 : 639 - 643
[22] SYNTHESIS OF NEW CONDENSED DERIVATIVES OF PYRANO[4,3-b]THIENO[3,2-e]PYRIDINE AND PYRIDO[3′,2′:4,5]THIENO[3,2-d]PYRIMIDINE
Dabaeva, V. V.
Bagdasaryan, M. R.
Noravyan, A. S.
CHEMISTRY OF HETEROCYCLIC COMPOUNDS, 2011, 47 (05) : 639 - 643
[23] SYNTHESIS OF 6,7-DIHYDRO-5H-THIOPYRANO[2,3-d]PYRIMIDIN-5-ONE DERIVATIVES STARTING WITH 4,6-DICHLORO-2-(METHYLSULFANYL)PYRIMIDINE
Kobayashi, Kazuhiro
Ono, Ryoga
Ishitobi, Kouki
Murayama, Ikuma
Hiyoshi, Hidetaka
Umezu, Kazuto
HETEROCYCLES, 2018, 96 (02) : 287 - 296
[24] Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: Novel VEGFR2 kinase inhibitors binding to inactive kinase conformation
Oguro, Yuya
Miyamoto, Naoki
Okada, Kengo
Takagi, Terufumi
Iwata, Hidehisa
Awazu, Yoshiko
Miki, Hiroshi
Hori, Akira
Kamiyama, Keiji
Imamura, Shinichi
BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (20) : 7260 - 7273
[25] One-Pot Synthesis of Thieno[2,3-b]pyridine and Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine Derivatives
I. V. Dyachenko
V. D. Dyachenko
P. V. Dorovatovsky
V. N. Khrustalev
V. G. Nenajdenko
Russian Journal of Organic Chemistry, 2020, 56 : 974 - 982
[26] One-Pot Synthesis of Thieno[2,3-b]pyridine and Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine Derivatives
Dyachenko, I. V.
Dyachenko, V. D.
Dorovatovsky, P. V.
Khrustalev, V. N.
Nenajdenko, V. G.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 2020, 56 (06) : 974 - 982
[27] Synthesis and biological evaluation of pyrido[3′,2':4,5]furo [3,2-d]pyrimidine derivatives as novel PI3 kinase p110α inhibitors
Hayakawa, Masahiko
Kaizawa, Hiroyuki
Moritomo, Hiroyuki
Koizumi, Tomonobu
Ohishi, Takahide
Yamano, Mayumi
Okada, Minoru
Ohta, Mitsuaki
Tsukamoto, Shin-ichi
Raynaud, Florence I.
Workman, Paul
Waterfield, Michael D.
Parker, Peter
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (09) : 2438 - 2442
[28] 3-(4-Fluorophenyl)-2-(4-methoxyphenoxy)-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile
Zeng, Guo-Ping
Yan, Shi-Rong
ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2008, 64 : O1680 - U1250
[29] Discovery and SAR study of 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-ones as soluble and highly potent PDE7 inhibitors
Endo, Yusuke
Kawai, Kentaro
Asano, Takeshi
Amano, Seiji
Asanuma, Yoshihito
Sawada, Keisuke
Ogura, Keiji
Nagata, Naoya
Ueo, Noriko
Takahashi, Nobuaki
Sonoda, Yo
Kamei, Noriyuki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (03) : 649 - 653
[30] 2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy
Endo, Yusuke
Kawai, Kentaro
Asano, Takeshi
Amano, Seiji
Asanuma, Yoshihito
Sawada, Keisuke
Onodera, Yuuta
Ueo, Noriko
Takahashi, Nobuaki
Sonoda, Yo
Kamei, Noriyuki
Irie, Tetsumi
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (09) : 1910 - 1914

← 1 2 3 4 5 →