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We report herein the potential of colony-stimulating factor-1 receptor (CSF1R) inhibitors as therapeutic agents in neuroinflammatory diseases, with a focus on Alzheimer's disease (AD). Employing a carefully modified scaffold, N -(4-heterocycloalkyl-2-cycloalkylphenyl)-5-methylisoxazole-3-carboxamide, we identify highly selective and potent CSF1R inhibitors─ 7dr i and 7ds i . Molecular docking studies shed light on the binding modes of these key compounds within the CSF1R binding site. Remarkably, kinome-wide selectivity assessment underscores the impressive specificity of 7dr i for CSF-1R. Notably, 7dr i emerges as a potent CSF-1R inhibitor with favorable cellular activity and minimal cytotoxicity among the synthesized compounds. Demonstrating efficacy in inhibiting CSF1R phosphorylation in microglial cells and successfully mitigating neuroinflammation in an in vivo LPS-induced model, 7dr i establishes itself as a promising antineuroinflammatory agent.

This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC 50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases., Competing Interests: Declaration of Competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jung-Mi Hah reports financial support was provided by National Research Foundation., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

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 IC 50 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jung-Mi Hah reports financial support was provided by National Research Foundation., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC50 = 9.7 nM), as well as neuroprotective effects against Aβ-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (−10 fold). [ABSTRACT FROM AUTHOR]

Despite innumerable efforts to develop effective therapeutics, it is difficult to achieve breakthrough treatments for Alzheimer's disease (AD), and the main reason is probably the absence of a clear target. Here, we reveal c-Jun N-terminal kinase 3 (JNK3), a protein kinase explicitly expressed in the brain and involved in neuronal apoptosis, with a view toward providing effective treatment for AD. For many years, we have worked on JNK3 inhibitors and have discovered 2-aryl-1-pyrimidinyl-1 H -imidazole-5-yl acetonitrile-based JNK3 inhibitors with superb potency (IC 50 < 1.0 nM) and excellent selectivity over other protein kinases including isoforms JNK1 (>300 fold) and JNK2 (∼10 fold). Based on in vitro biological activity and DMPK properties, the lead compounds were selected for further in vivo studies. We confirmed that repeat administration of JNK3 inhibitors improved cognitive memory in APP/PS1 and the 3xTg mouse model. Overall, our results show that JNK3 could be a potential target protein for AD. [Display omitted] • 2-Aryl-1-pyrimidinyl-1 H -imidazole-yl acetonitrile were designed as JNK3 inhibitors. • Compound 15d exhibited superb potency of 1 nM and excellent isoform selectivity. • Compound 15g exhibited potency of 4 nM and good oral pharmacokinetic profile. • JNK3 inhibitors showed neuroprotective effect against Aβ induced cellular apoptosis. • Administration of 15d / 15g improved cognitive function of AD mice in havioral test. [ABSTRACT FROM AUTHOR]