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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...

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Autores principales: Zheng, Ke, Iqbal, Sarah, Hernandez, Pamela, Park, HaJeung, LoGrasso, Philip V., Feng, Yangbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
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.
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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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