Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration

被引：33

作者：

Probst, Gary D. ^{[1
]}

Bowers, Simeon ^{[1
]}

Sealy, Jennifer M. ^{[1
]}

Truong, Anh P. ^{[1
]}

Hom, Roy K. ^{[1
]}

Galemmo, Robert A., Jr. ^{[1
]}

Konradi, Andrei W. ^{[1
]}

Sham, Hing L. ^{[1
,3
]}

Quincy, David A. ^{[3
]}

Pan, Hu ^{[4
]}

Yao, Nanhua ^{[4
]}

Lin, May ^{[4
]}

Toth, Gergley ^{[4
]}

Artis, Dean R. ^{[4
]}

Zmolek, Wes ^{[5
]}

Wong, Karina ^{[5
]}

Qin, Ann ^{[5
]}

Lorentzen, Colin ^{[5
]}

Nakamura, David F. ^{[5
]}

Quinn, Kevin P. ^{[5
]}

Sauer, John-Michael ^{[5
]}

Powell, Kyle ^{[2
]}

Ruslim, Lany ^{[2
]}

Wright, Sarah ^{[2
]}

Chereau, David ^{[2
]}

Ren, Zhao ^{[2
]}

Anderson, John P. ^{[2
]}

Bard, Frederique ^{[2
]}

Yednock, Ted A. ^{[1
,2
,3
,4
,5
]}

Griswold-Prenner, Irene ^{[2
]}

机构：

[1] Elan Pharmaceut, Dept Med Chem, San Francisco, CA 94080 USA

[2] Elan Pharmaceut, Dept Biol, San Francisco, CA 94080 USA

[3] Elan Pharmaceut, Dept Proc & Analyt Chem, San Francisco, CA 94080 USA

[4] Elan Pharmaceut, Dept Mol Design, San Francisco, CA 94080 USA

[5] Elan Pharmaceut, Dept Lead Finding Drug Disposit & Safety Evaluat, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 01期

关键词：

JNK inhibitor; Selective; Kinase; SMALL-MOLECULE INHIBITORS; P38 MAP KINASE; SIGNALING PATHWAYS; ARYL HALIDES; DESIGN; STRATEGIES; MODEL; COMPLEXES; AS601245; TARGET;

D O I：

10.1016/j.bmcl.2010.11.010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38 alpha and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-pi stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-beta in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：315 / 319

页数：5

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