Development of Potent, Selective cPLA2 Inhibitors for Targeting Neuroinflammation in Alzheimer’s Disease and Other Neurodegenerative Disorders

Chronic neuroinflammation plays a key role in the progression of Alzheimer’s disease (AD), and the cytosolic calcium-dependent phospholipase A2 (cPLA ₂ ) enzyme is a critical mediator of inflammatory lipid signaling pathways. Here we investigate the therapeutic potential of novel cPLA ₂ inhibitors in modulating neuroinflammation in AD. By leveraging the giga-scale V-SYNTHES 2.0 virtual screening in on-demand chemical space and conducting two rounds of optimization for potency and selectivity, we have identified BRI-50460, achieving an IC ₅₀ of 0.88 nM in cellular assays of cPLA ₂ activity. In vivo studies revealed favorable brain-to-plasma ratios, highlighting the ability of BRI-50460 to penetrate the central nervous system, potentially modulating neuroinflammatory pathways and restoring lipid homeostasis. In cultured astrocytes and neurons derived from human induced pluripotent stem cells, BRI-50460 mitigates the effects of amyloid beta 42 oligomers on cPLA ₂ activation, tau hyperphosphorylation, and synaptic and dendritic reduction. Our results suggest that small molecule inhibitors of the cPLA ₂ enzyme can modulate the downstream inflammatory lipid signaling pathways, offering a promising therapeutic strategy for AD and other neurodegenerative diseases.