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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.
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页码:443 / 456
页数:14
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