Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor

We designed and synthesized 1-pyrimidinyl-2-aryl-4, 6-dihydropyrrolo [3,4-d] imidazole-5(1H)-carboxamide derivatives as selective inhibitors of c-Jun-N-terminal Kinase 3 (JNK3), a target for the treatment of neurodegenerative diseases. Based on the compounds found in previous studies, a novel scaffo...

Descripción completa

Detalles Bibliográficos
Autores principales: Jang, Miyoung, Oh, Youri, Cho, Hyunwook, Yang, Songyi, Moon, Hyungwoo, Im, Daseul, Hah, Jung-Mi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084495/
https://www.ncbi.nlm.nih.gov/pubmed/32131443
http://dx.doi.org/10.3390/ijms21051698
_version_ 1783508734964662272
author Jang, Miyoung
Oh, Youri
Cho, Hyunwook
Yang, Songyi
Moon, Hyungwoo
Im, Daseul
Hah, Jung-Mi
author_facet Jang, Miyoung
Oh, Youri
Cho, Hyunwook
Yang, Songyi
Moon, Hyungwoo
Im, Daseul
Hah, Jung-Mi
author_sort Jang, Miyoung
collection PubMed
description We designed and synthesized 1-pyrimidinyl-2-aryl-4, 6-dihydropyrrolo [3,4-d] imidazole-5(1H)-carboxamide derivatives as selective inhibitors of c-Jun-N-terminal Kinase 3 (JNK3), a target for the treatment of neurodegenerative diseases. Based on the compounds found in previous studies, a novel scaffold was designed to improve pharmacokinetic characters and activity, and compound 18a, (R)-1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-4,6-dihydro pyrrolo [3,4-d]imidazole-5(1H)-carboxamide, showed the highest IC(50) value of 2.69 nM. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases, having mild activity against JNK2, RIPK3, and GSK3β, which also known to involve in neuronal apoptosis.
format Online
Article
Text
id pubmed-7084495
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-70844952020-03-24 Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor Jang, Miyoung Oh, Youri Cho, Hyunwook Yang, Songyi Moon, Hyungwoo Im, Daseul Hah, Jung-Mi Int J Mol Sci Article We designed and synthesized 1-pyrimidinyl-2-aryl-4, 6-dihydropyrrolo [3,4-d] imidazole-5(1H)-carboxamide derivatives as selective inhibitors of c-Jun-N-terminal Kinase 3 (JNK3), a target for the treatment of neurodegenerative diseases. Based on the compounds found in previous studies, a novel scaffold was designed to improve pharmacokinetic characters and activity, and compound 18a, (R)-1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-4,6-dihydro pyrrolo [3,4-d]imidazole-5(1H)-carboxamide, showed the highest IC(50) value of 2.69 nM. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases, having mild activity against JNK2, RIPK3, and GSK3β, which also known to involve in neuronal apoptosis. MDPI 2020-03-02 /pmc/articles/PMC7084495/ /pubmed/32131443 http://dx.doi.org/10.3390/ijms21051698 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jang, Miyoung
Oh, Youri
Cho, Hyunwook
Yang, Songyi
Moon, Hyungwoo
Im, Daseul
Hah, Jung-Mi
Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor
title Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor
title_full Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor
title_fullStr Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor
title_full_unstemmed Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor
title_short Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor
title_sort discovery of 1-pyrimidinyl-2-aryl-4,6-dihydropyrrolo [3,4-d]imidazole-5(1h)-carboxamide as a novel jnk inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084495/
https://www.ncbi.nlm.nih.gov/pubmed/32131443
http://dx.doi.org/10.3390/ijms21051698
work_keys_str_mv AT jangmiyoung discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor
AT ohyouri discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor
AT chohyunwook discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor
AT yangsongyi discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor
AT moonhyungwoo discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor
AT imdaseul discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor
AT hahjungmi discoveryof1pyrimidinyl2aryl46dihydropyrrolo34dimidazole51hcarboxamideasanoveljnkinhibitor

Ejemplares similares