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

被引：26

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

共 15 条

[1] SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase [J].

Bennett, BL ;

Sasaki, DT ;

Murray, BW ;

O'Leary, EC ;

Sakata, ST ;

Xu, WM ;

Leisten, JC ;

Motiwala, A ;

Pierce, S ;

Satoh, Y ;

Bhagwat, SS ;

Manning, AM ;

Anderson, DW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (24) :13681-13686

[2] Therapeutic promise of JNK ATP-noncompetitive inhibitors [J].

Bogoyevitch, MA .

TRENDS IN MOLECULAR MEDICINE, 2005, 11 (05) :232-239

[3] Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases [J].

Choukroun, G ;

Hajjar, R ;

Fry, S ;

del Monte, F ;

Haq, S ;

Guerrero, JL ;

Picard, M ;

Rosenzweig, A ;

Force, T .

JOURNAL OF CLINICAL INVESTIGATION, 1999, 104 (04) :391-398

[4] Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease [J].

Cook, SA ;

Sugden, PH ;

Clerk, A .

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1999, 31 (08) :1429-1434

[5] Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase [J].

Gaillard, P ;

Jeanclaude-Etter, I ;

Ardissone, V ;

Arkinstall, S ;

Cambet, Y ;

Camps, M ;

Chabert, C ;

Church, D ;

Cirillo, R ;

Gretener, D ;

Halazy, S ;

Nichols, A ;

Szyndralewiez, C ;

Vitte, PA ;

Gotteland, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (14) :4596-4607

[6]

Gong XH, 2000, CIRCULATION, V102, P216

[7] Targeting JNK for therapeutic benefit: From JuNK to gold? [J].

Manning, AM ;

Davis, RJ .

NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (07) :554-565

[8] Pressure overload per se rather than cardiac angiotensin converting enzyme activity may be important in the development of rat cardiac hypertrophy [J].

Mukawa, H ;

Toki, Y ;

Shimauchi, A ;

Matsui, H ;

Morishima, I ;

Okumura, K ;

Ito, T ;

Hayakawa, T .

JOURNAL OF HYPERTENSION, 1997, 15 (09) :1027-1032

[9] Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects [J].

Petrich, BG ;

Eloff, BC ;

Lerner, DL ;

Kovacs, A ;

Saffitz, JE ;

Rosenbaum, DS ;

Wang, YB .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (15) :15330-15338

[10] c-Jun N-terminal kinase activation mediates downregulation of connexin43 in cardiomyocytes [J].

Petrich, BG ;

Gong, XH ;

Lerner, DL ;

Wang, X ;

Brown, JH ;

Saffitz, JE ;

Wang, YB .

CIRCULATION RESEARCH, 2002, 91 (07) :640-647

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