Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors

被引：26

作者：

Liu, M ^{[1
]}

Xin, ZL ^{[1
]}

Clampit, JE ^{[1
]}

Wang, SY ^{[1
]}

Gum, RJ ^{[1
]}

Haasch, DL ^{[1
]}

Trevillyan, JM ^{[1
]}

Abad-Zapatero, C ^{[1
]}

Fry, EH ^{[1
]}

Sham, HL ^{[1
]}

Liu, G ^{[1
]}

机构：

[1] Abbott Labs, Metab Dis Res, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 10期

关键词：

JNK; diabetes; obesity; pyrazoloquinolinones;

D O I：

10.1016/j.bmcl.2006.02.046

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as c-Jun-N-terminal kinase (JNK) inhibitors is described. These compounds were synthesized via the condensation of 2-nitrobenzaldehydes and hydroxypyrazoles. The structure-activity relationships (SAR) and kinase selectivity profile of the inhibitors are also discussed. Compound 16 was identified as a potent JNK inhibitor with good cellular potency. (C) 2006 Elsevier Ltd. All rights reserved.

引用

页码：2590 / 2594

页数：5

共 16 条

[1] The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307 [J].

Aguirre, V ;

Uchida, T ;

Yenush, L ;

Davis, R ;

White, MF .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) :9047-9054

[2] The specificities of protein kinase inhibitors: an update [J].

Bain, J ;

McLauchlan, H ;

Elliott, M ;

Cohen, P .

BIOCHEMICAL JOURNAL, 2003, 371 :199-204

[3] JNK: a new therapeutic target for diabetes [J].

Bennett, BL ;

Satoh, Y ;

Lewis, AJ .

CURRENT OPINION IN PHARMACOLOGY, 2003, 3 (04) :420-425

[4] 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

[5] TRANSCRIPTION FACTOR ATF2 REGULATION BY THE JNK SIGNAL-TRANSDUCTION PATHWAY [J].

GUPTA, S ;

CAMPBELL, D ;

DERIJARD, B ;

DAVIS, RJ .

SCIENCE, 1995, 267 (5196) :389-393

[6] A central role for JNK in obesity and insulin resistance [J].

Hirosumi, J ;

Tuncman, G ;

Chang, LF ;

Görgün, CZ ;

Uysal, KT ;

Maeda, K ;

Karin, M ;

Hotamisligil, GS .

NATURE, 2002, 420 (6913) :333-336

[7] Synthesis of 3-ethoxycarbonyl-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes [J].

Kim, JN ;

Lee, KY ;

Kim, HS ;

Kim, TY .

ORGANIC LETTERS, 2000, 2 (03) :343-345

[8] SUBSTITUENT INTERACTIONS IN ORTHO-SUBSTITUTED NITROBENZENES .4. [J].

LOUDON, JD ;

TENNANT, G .

JOURNAL OF THE CHEMICAL SOCIETY, 1962, (AUG) :3092-&

[9]

LOUDON JD, 1960, J CHEM SOC, P3470, DOI 10.1039/jr9600003470

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

Manning, AM ;

Davis, RJ .

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

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