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Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives
[Image: see text] 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 selectivi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266361/ https://www.ncbi.nlm.nih.gov/pubmed/25393557 http://dx.doi.org/10.1021/jm501256y |
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author | Zheng, Ke Iqbal, Sarah Hernandez, Pamela Park, HaJeung LoGrasso, Philip V. Feng, Yangbo |
author_facet | Zheng, Ke Iqbal, Sarah Hernandez, Pamela Park, HaJeung LoGrasso, Philip V. Feng, Yangbo |
author_sort | Zheng, Ke |
collection | PubMed |
description | [Image: see text] 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 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors. |
format | Online Article Text |
id | pubmed-4266361 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-42663612015-11-13 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 J Med Chem [Image: see text] 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 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors. American Chemical Society 2014-11-13 2014-12-11 /pmc/articles/PMC4266361/ /pubmed/25393557 http://dx.doi.org/10.1021/jm501256y Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Zheng, Ke Iqbal, Sarah Hernandez, Pamela Park, HaJeung LoGrasso, Philip V. Feng, Yangbo Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives |
title | Design and Synthesis of Highly
Potent and Isoform
Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives |
title_full | Design and Synthesis of Highly
Potent and Isoform
Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives |
title_fullStr | Design and Synthesis of Highly
Potent and Isoform
Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives |
title_full_unstemmed | Design and Synthesis of Highly
Potent and Isoform
Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives |
title_short | Design and Synthesis of Highly
Potent and Isoform
Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives |
title_sort | design and synthesis of highly
potent and isoform
selective jnk3 inhibitors: sar studies on aminopyrazole derivatives |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266361/ https://www.ncbi.nlm.nih.gov/pubmed/25393557 http://dx.doi.org/10.1021/jm501256y |
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