Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas as potent inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2)

被引：17

作者：

Lin, Songnian ^{[1
]}

Lombardo, Matthew ^{[1
]}

Malkani, Sunita ^{[1
]}

Hale, Jeffrey J. ^{[1
]}

Mills, Sander G. ^{[1
]}

Chapman, Kevin ^{[1
]}

Thompson, James E. ^{[1
]}

Zhang, Wen Xiao ^{[1
]}

Wang, Ruixiu ^{[1
]}

Cubbon, Rose M. ^{[1
]}

O'Neill, Edward A. ^{[1
]}

Luell, Silvi ^{[1
]}

Carballo-Jane, Ester ^{[1
]}

Yang, Lihu ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 12期

关键词：

MAPKAP kinase 2; MK-2; TNF alpha; Inflammation; Rheumatoid arthritis; Aminopyrazine; Thiourea; RHEUMATOID-ARTHRITIS;

D O I：

10.1016/j.bmcl.2009.04.088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas are described as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). These compounds demonstrate potent in vitro activity against the enzyme with IC50 values as low as 15 nM, and suppress expression of TNF alpha in THP-1 cells and in vivo in an acute inflammation model in mice. The synthesis, structure-activity relationship (SAR), and biological evaluation of these compounds are discussed. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3238 / 3242

页数：5

共 50 条

[21] The MAP kinase-activated protein kinase 2 (MK2) contributes to the Shiga toxin-induced inflammatory response
Saenz, Jose B.
Li, Jinmei
Haslam, David B.
CELLULAR MICROBIOLOGY, 2010, 12 (04) : 516 - 529
[22] Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo(1,5-a)pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization Approach
Kosugi, Tomomi
Mitchell, Dale R.
Fujino, Aiko
Imai, Minoru
Kambe, Mika
Kobayashi, Shinji
Makino, Hiroaki
Matsueda, Yohei
Oue, Yasuhiro
Komatsu, Kanji
Imaizumi, Keiichiro
Sakai, Yuri
Sugiura, Satoshi
Takenouchi, Osami
Unoki, Gen
Yamakoshi, Yuko
Cunliffe, Vicky
Frearson, Julie
Gordon, Richard
Harris, C. John
Kalloo-Hosein, Heidi
Le, Joelle
Patel, Gita
Simpson, Donald J.
Sherborne, Brad
Thomas, Peter S.
Suzuki, Naotaka
Takimoto-Kamimura, Midori
Kataoka, Ken-ichiro
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (15) : 6700 - 6715
[23] Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor-induced interleukin-6 expression via human antigen R
Xu Jin
Su Xin
Shi Jia-xin
Sun He
Wu Ting
Shi Yi
CHINESE MEDICAL JOURNAL, 2013, 126 (22) : 4322 - 4326
[24] Induction of prostaglandin endoperoxide synthase 2 by mitogen-activated protein kinase cascades
McGinty, A
Foschi, M
Chang, YWE
Han, JH
Dunn, MJ
Sorokin, A
BIOCHEMICAL JOURNAL, 2000, 352 : 419 - 424
[25] Distinct Functions of the Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinases MK2 and MK3 MK2 MEDIATES LIPOPOLYSACCHARIDE-INDUCED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION BY PREVENTING NEGATIVE REGULATORY EFFECTS OF MK3
Ehlting, Christian
Ronkina, Natalia
Boehmer, Oliver
Albrecht, Ute
Bode, Konrad A.
Lang, Karl S.
Kotlyarov, Alexey
Radzioch, Danuta
Gaestel, Matthias
Haeussinger, Dieter
Bode, Johannes G.
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (27) : 24113 - 24124
[26] Revisiting p38 Mitogen-Activated Protein Kinases (MAPK) in Inflammatory Arthritis: A Narrative of the Emergence of MAPK-Activated Protein Kinase Inhibitors (MK2i)
Ganguly, Payal
Macleod, Tom
Wong, Chi
Harland, Mark
Mcgonagle, Dennis
PHARMACEUTICALS, 2023, 16 (09)
[27] Differential Effects of p38 Mitogen-Activated Protein Kinase and Cyclooxygenase 2 Inhibitors in a Model of Cardiovascular Disease
Willette, Robert N.
Eybye, Marianne E.
Olzinski, Alan R.
Behm, David J.
Aiyar, Nambi
Maniscalco, Kristeen
Bentley, Ross G.
Coatney, Robert W.
Zhao, Shufang
Westfall, Timothy D.
Doe, Chris P.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2009, 330 (03) : 964 - 970
[28] Association of Common Genetic Variants in Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 with Type 2 Diabetes Mellitus in a Chinese Han Population
Li, Ting-Ting
Qiao, Hong
Tong, Hui-Xin
Zhuang, Tian-Wei
Wang, Tong-Tong
CHINESE MEDICAL JOURNAL, 2016, 129 (10) : 1179 - 1184
[29] MiR-20a-5p facilitates cartilage repair in osteoarthritis via suppressing mitogen-activated protein kinase kinase kinase 2
Liu, Jiazhi
Tang, Guo
Liu, Wenjun
Zhou, Yi
Fan, Cunyi
Zhang, Wei
BIOENGINEERED, 2022, 13 (05) : 13801 - 13814
[30] 1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase
Lumeras, Wenceslao
Vidal, Laura
Vidal, Bernat
Balague, Cristina
Orellana, Adelina
Maldonado, Monica
Dominguez, Maria
Segarra, Victor
Caturla, Francisco
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (22) : 7899 - 7910

← 1 2 3 4 5 →