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

被引：25

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 08期

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

页码：4715 / 4732

页数：18

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