CNS-Active p38α MAPK Inhibitors for the Management of Neuroinflammatory Diseases: Medicinal Chemical Properties and Therapeutic Capabilities

• Published in: Molecular neurobiology 2024-07, Vol.61 (7), p.3911-3933
• Main Authors: Valipour, Mehdi, Mohammadi, Maryam, Valipour, Habib
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Cell Biology; Central nervous system; Central Nervous System - drug effects; Chemistry, Pharmaceutical - methods; Crystal structure; Humans; Inflammation; Kinases; MAP kinase; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 14 - chemistry; Mitogen-Activated Protein Kinase 14 - metabolism; Neurobiology; Neurodegenerative diseases; Neuroinflammatory Diseases - drug therapy; Neurology; Neurosciences; Physicochemical properties; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-023-03829-3

During the last two decades, many p38α mitogen-activated protein kinase (p38α MAPK) inhibitors have been developed and tested in preclinical/clinical studies for the treatment of various disorders, especially problems with the origin of inflammation. Previous studies strongly suggest the involvement of the p38α MAPK pathway in the pathogenesis of neurodegenerative disorders. Despite the significant progress made in this field, so far no studies have focused on p38α MAPK inhibitors that have the capability to be used for the treatment of neurodegenerative disorders. In the present review, we evaluated a wide range of well-known p38α MAPK inhibitors (more than 140 small molecules) by measuring key physicochemical parameters to identify those capable of successfully crossing the blood-brain barrier (BBB). As a result, we identify about 50 naturally occurring and synthetic p38α MAPK inhibitors with high potential to cross the BBB, which can be further explored in the future for the treatment of neurodegenerative disorders. In addition, a detailed analysis of the previously released X-ray crystal structure of the inhibitors in the active site of the p38α MAPK enzyme revealed that some residues such as Met109 play a critical role in the occurrence of effective interactions by constructing strong H-bonds. This study can encourage scientists to focus more on the design, production, and biological evaluation of new central nervous system (CNS)-active p38α MAPK inhibitors in the future.