Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1)

被引:24
|
作者
Asano, Yasutomi [1 ]
Kitamura, Shuji [1 ]
Ohra, Taiichi [1 ]
Aso, Kazuyoshi [1 ]
Igata, Hideki [3 ]
Tamura, Tomoko [3 ]
Kawamoto, Tomohiro [2 ]
Tanaka, Toshimasa [2 ]
Sogabe, Satoshi [2 ]
Matsumoto, Shin-ichi [2 ]
Yamaguchi, Masashi [2 ]
Kimura, Hiroyuki [2 ]
Itoh, Fumio [1 ]
机构
[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Med Chem Res Labs, Yodogawa Ku, Osaka 5328686, Japan
[2] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Discovery Res Ctr, Yodogawa Ku, Osaka 5328686, Japan
[3] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Pharmacol Res Labs 1, Yodogawa Ku, Osaka 5328686, Japan
关键词
JNK; JNK inhibitor; isoquinolone; SAR; Modeling; heart failure; cardiac hypertrophy; X-ray crystallography;
D O I
10.1016/j.bmc.2008.02.027
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modi. cation at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed. (c) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:4715 / 4732
页数:18
相关论文
共 50 条
  • [1] Discovery, Synthesis, and Biological Evaluation of a Novel Group of Selective Inhibitors of Filoviral Entry
    Yermolina, Maria V.
    Wang, Jizhen
    Caffrey, Michael
    Rong, Lijun L.
    Wardrop, Duncan J.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (03) : 765 - 781
  • [2] Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor
    Li, Qi
    Xing, Shuaishuai
    Chen, Ying
    Liao, Qinghong
    Xiong, Baichen
    He, Siyu
    Lu, Weixuan
    Liu, Yang
    Yang, Hongyu
    Li, Qihang
    Feng, Feng
    Liu, Wenyuan
    Chen, Yao
    Sun, Haopeng
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (17) : 10030 - 10044
  • [3] Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors
    Abu Rabah, Reinad R.
    Sebastian, Anusha
    Vunnam, Srinivasulu
    Sultan, Shaista
    Tarazi, Hamadeh
    Anbar, Hanan S.
    Shehata, Mahmoud K.
    Zaraei, Seyed-Omar
    Elgendy, Sara M.
    Al Shamma, Salma A.
    Omar, Hany A.
    Al-Tel, Taleb H.
    El-Gamal, Mohammed, I
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2022, 69
  • [4] Design, synthesis, and biological evaluation of novel highly selective non-carboxylic acid FABP1 inhibitors
    Chen, Lianru
    Wang, Bin
    Li, Hongming
    Mao, Jianming
    Liang, Zhiling
    Chen, Ya
    Yu, Mingyang
    Liu, Yuxia
    Liao, Zibin
    Yang, Yuanqian
    Wu, Xiaojing
    Wang, Huazheng
    Yang, Yonghong
    Xiang, Ruojing
    Zhang, Luyong
    Li, Zheng
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 276
  • [5] Discovery of novel and highly selective allosteric inhibitors of PAK1
    Lindvall, Mika
    Karpov, Alexei
    Bellamacina, Cornelia
    Daniel, Dylan
    Fabbro, Doriano
    Fernandez, Cesar
    Jacob, Sandra
    Jahnke, Wolfgang
    Moebitz, Henrik
    Pecchi, Sabina
    Pecchi, Sabina
    Shoemaker, Kevin
    Wang, John
    Breitenstein, Werner
    Gutmann, Sascha
    Lagasse, Stephanie
    Machajewski, Timothy
    Marzinzik, Andreas
    Galuba, Inga
    Trappe, Joerg
    Crawford, Kenneth
    Voliva, Charles
    Lai, Albert
    Hinh, Linda
    Rummel, Gabriele
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 246
  • [6] Design, synthesis and biological evaluation of highly potent and selective CYP1B1 inhibitors
    Zhang, Haoyu
    Xu, Ping
    Wang, Ting
    Wang, Shiyu
    Li, Weixia
    Mao, Jianping
    Wang, Jian
    Zhang, Fengjiao
    Cheng, Maosheng
    [J]. NEW JOURNAL OF CHEMISTRY, 2023, 47 (12) : 5680 - 5690
  • [7] Discovery of resveratrol derivatives as novel LSD1 inhibitors: Design, synthesis and their biological evaluation
    Duan, Ying-Chao
    Guan, Yuan-Yuan
    Zhai, Xiao-Yu
    Ding, Li-Na
    Qin, Wen-Ping
    Shen, Dan-Dan
    Liu, Xue-Qi
    Sun, Xu-Dong
    Zheng, Yi-Chao
    Liu, Hong-Min
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2017, 126 : 246 - 258
  • [8] Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors
    Hierold, Judith
    Baek, Sohee
    Rieger, Rene
    Lim, Tae-Gyu
    Zakpur, Saman
    Arciniega, Marcelino
    Lee, Ki Won
    Huber, Robert
    Tietze, Lutz F.
    [J]. CHEMISTRY-A EUROPEAN JOURNAL, 2015, 21 (47) : 16887 - 16894
  • [9] Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers
    Nishida, Haruyuki
    Hasuoka, Atsushi
    Arikawa, Yasuyoshi
    Kurasawa, Osamu
    Hirase, Keizo
    Inatomi, Nobuhiro
    Hori, Yasunobu
    Sato, Fumihiko
    Tarui, Naoki
    Imanishi, Akio
    Kondo, Mitsuyo
    Takagi, Terufumi
    Kajino, Masahiro
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (12) : 3925 - 3938
  • [10] Discovery and biological evaluation of a novel, potent and selective series of ACC2 inhibitors
    Gu, Yu Gui
    Weitzberg, Moshe
    Clark, Richard F.
    Xu, Xiangdong
    Li, Qun
    Zhang, Tianyuan
    Hansen, T. Matthew
    Keyes, Robert F.
    Liu, Gang
    Xin, Zhili
    Wang, Xiaojun
    Wang, Rongqi
    McNally, Teresa
    Zinker, Bradley A.
    Dickinson, Bob W.
    Lubbers, Nathan L.
    Yang, Yi
    Beno, David W. A.
    Widomski, Deborah L.
    Waring, Jeffrey F.
    Carroll, Sherry L.
    Healan-Greenberg, Christine H.
    Blomme, Eric A.
    Frevert, Ernst U.
    Beutel, Bruce A.
    Sham, Hing L.
    Camp, Heidi S.
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 233 : 614 - 614