Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 하정미 | - |
dc.date.accessioned | 2024-04-04T02:37:20Z | - |
dc.date.available | 2024-04-04T02:37:20Z | - |
dc.date.issued | 2022-11-10 | - |
dc.identifier.citation | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | en_US |
dc.identifier.issn | 0223-5234 | en_US |
dc.identifier.uri | https://www.sciencedirect.com/science/article/pii/S0223523422008194 | en_US |
dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/189607 | - |
dc.description.abstract | JNK3 is a key factor driving the pathophysiology of neuronal apoptosis. Since demonstrating the therapeutic potential of JNK3 inhibitors in Alzheimer's disease, we aimed to broaden their chemical diversity for drug development. In continuation with our previous research, a series of compounds with the tetrahydrocyclopenta [d]imidazole scaffold as a core moiety was developed as JNK3 inhibitors based on in silico modeling analysis. The biochemical kinase assay results revealed that the JNK3 inhibitory effects and isoform selectivity of the compounds developed in this study were significantly higher than that of previously developed inhibitors. In particular, the IC50 values of compounds 18c, 19c, 22b, and 26c, which exhibited excelled isoform selectivity, against JNK3 were 0.716, 0.564, 0.379, and 0.779 nM, respectively, which were more potent than those of any known JNK3 inhibitors. Additionally, compounds 18c, 18c, 22b, and 22c effectively protected the neuronal cells against amyloid beta-induced apoptosis. Docking studies indicated that the tetrahydrocyclopenta[d]imidazole scaffold retained all the optimal interactions. Meanwhile, BBB PAMPA and ADME prediction suggested that the tested compounds had a favorable BBB permeability and pharmacokinetic profile. Therefore, the tetrahydrocyclopenta[d]imidazole scaffold is a promising candidate for developing JNK3 inhibitors. In particular, compound 22b is a potential starting point for the preclinical optimization of novel JNK3 inhibitors. | en_US |
dc.description.sponsorship | This work was supported by a National Research Foundation of Korea grant NRF-2019M3A9A8066500 (J.-M.H.) NRF-2020R1A6A1A03042854 (Center for Proteinopathy), NRF-2021R1A2C2007159 (J.-M.H.) and supported by an Institute of Information and Communications Technology Planning and Evaluation (IITP) grant funded by the Korean government (MSIT) (No. 2020-0-01343). | en_US |
dc.language | en_US | en_US |
dc.publisher | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | en_US |
dc.relation.ispartofseries | v. 245, NO 1;114917-114931 | - |
dc.subject | JNK3 | en_US |
dc.subject | Alzheimer’s disease | en_US |
dc.subject | tetrahydrocyclopenta[d]imidazole | en_US |
dc.subject | Neurodegenerative diseases | en_US |
dc.subject | Structure-activity relationship | en_US |
dc.title | Novel 1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carboxamide-based JNK3 inhibitors: Design, synthesis, molecular docking, and therapeutic potential in neurodegenerative diseases | en_US |
dc.type | Article | en_US |
dc.relation.no | 1 | - |
dc.relation.volume | 245 | - |
dc.identifier.doi | https://doi.org/10.1016/j.ejmech.2022.114917 | en_US |
dc.relation.page | 114917-114931 | - |
dc.relation.journal | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | - |
dc.contributor.googleauthor | Jun, Joonhong | - |
dc.contributor.googleauthor | Baek, Jihyun | - |
dc.contributor.googleauthor | Kang, Dahyun | - |
dc.contributor.googleauthor | Moon, Hyungwoo | - |
dc.contributor.googleauthor | Kim, Hyejin | - |
dc.contributor.googleauthor | Cho, Hyunwook | - |
dc.contributor.googleauthor | Hah, Jung-Mi | - |
dc.relation.code | 2023041495 | - |
dc.sector.campus | E | - |
dc.sector.daehak | COLLEGE OF PHARMACY[E] | - |
dc.sector.department | DEPARTMENT OF PHARMACY | - |
dc.identifier.pid | jhah | - |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.