Tetra-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases

被引:41
作者
Muth, Felix [1 ]
Guenther, Marcel [1 ]
Bauer, Silke M. [1 ]
Doering, Eva [1 ]
Fischer, Sabine [1 ]
Maier, Julia [2 ]
Drueckes, Peter [3 ]
Koeppler, Juergen [3 ]
Trappe, Joerg [3 ]
Rothbauer, Ulrich [2 ]
Koch, Pierre [1 ]
Laufer, Stefan A. [1 ]
机构
[1] Univ Tubingen, Inst Pharmaceut Sci, Dept Pharmaceut & Med Chem, D-72076 Tubingen, Germany
[2] Univ Tubingen, Nat & Med Sci Inst, D-72770 Reutlingen, Germany
[3] Novartis Pharma AG, CH-4002 Basel, Switzerland
关键词
HUNTINGTONS-DISEASE; MAP KINASE; JNK; IMIDAZOLES; PATHWAYS; THERAPY; TARGETS; DESIGN;
D O I
10.1021/jm501557a
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38 alpha mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38 alpha MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38 alpha MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38 alpha, 30 nM) and 14d (IC50: JNK3, 26 nM; p38 alpha, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntingtons disease.
引用
收藏
页码:443 / 456
页数:14
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