C-Jun N-terminal kinase (JNK) is a member of mitogen-activated protein kinases (MAPKs) family, with three isoforms, JNK1, JNK2 and JNK3. Alzheimer's disease (AD) is a neurological disorder and the most common type of dementia. Two well-established AD pathologies are the deposition of Aβ amyloid plaques and neurofibrillary tangles caused by Tau hyperphosphorylation. JNK3 is involved in forming amyloid Aβ and neurofibrillary tangles, suggesting that JNK3 may represent a target to develop treatments for AD. Therefore, this review will discuss the roles of JNK3 in the pathogenesis and treatment of AD, and the latest progress in the development of JNK3 inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2022.106090 | DOI Listing |
Bioorg Chem
December 2024
Pharmaceutical Chemistry Department, Collage of Pharmaceutical Science and Drug Manufacturing, Misr University for Science and Technology, P.O. 77, 6th of October City, Giza, Egypt.
In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
December 2024
State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, West China Hospital, Sichuan University, No. 17, Section 3, Renmin South Road, 610041, Chengdu, China.
c-Jun N-terminal kinases (JNKs) including JNK1/2/3 are key members of mitogen-activated protein kinase family. Wherein JNK3 is specifically expressed in brain and emerges as therapeutic target, especially for neurodegenerative diseases. However, developing JNK3 selective inhibitors as chemical probes to investigate its therapeutic potential in diseases remains challenging.
View Article and Find Full Text PDFSelectivity is a primary focus in medicinal chemistry for ATP-competitive kinase inhibitors due to the highly conserved ATP binding pockets in the kinome. A decade of medicinal chemistry efforts has been carried out to develop selective inhibitors for JNKs, resulting in the identification of numerous promising scaffolds that even exhibit isoform selectivity. Thiophene-indazole is one of the scaffolds explored for isoform selectivity.
View Article and Find Full Text PDFNeurochem Int
October 2024
EBRI Rita Levi-Montalcini Foundation, Rome, Italy; Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy. Electronic address:
N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets.
View Article and Find Full Text PDFDrug Des Devel Ther
July 2024
Laboratory for Molecular Design & Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany.
Purpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SAr/SN).
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