1152841-43-4Relevant academic research and scientific papers
Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives
Zheng, Ke,Iqbal, Sarah,Hernandez, Pamela,Park, Hajeung,Lograsso, Philip V.,Feng, Yangbo
, p. 10013 - 10030 (2014)
The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure-activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 ? to explore the binding mode of aminopyrazole based JNK3 inhibitors.
HETEROCYCLYL PYRAZOLOPYRIMIDINE ANALOGUES AS JAK INHIBITORS
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Page/Page column 128, (2011/05/06)
The present invention relates to compounds of formula (I) wherein X1 to X5, Y, Z1 to Z3, and R have the meaning as cited in the description and the claims. Said compounds are useful as JAK inhibitors for the treatment or prophylaxis of immunological, inflammatory, autoimmune, allergic disorders, and immunologically-mediated diseases. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments.
