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 (cPLA₂) enzyme is a critical mediator of inflammatory lipid signaling pathways. Here we investigate the therapeutic potential of novel cPLA₂ inhibitors in modulating neuroinflammation in AD. By leveraging the giga-scale V-SYNTHES2 virtual screening in on-demand chemical space and conducting two rounds of optimization for potency and selectivity, we have identified BRI-50460, achieving an IC₅₀ of 0.88 nM in cellular assays that measure cPLA₂-mediated arachidonic acid release. In vivo studies revealed favorable brain-to-plasma ratios, highlighting the ability of BRI-50460 to penetrate the central nervous system, modulating neuroinflammatory pathways, and restoring lipid homeostasis. In astrocytes and neurons derived from human induced pluripotent stem cells, BRI-50460 mitigates the effects of amyloid beta 42 oligomers on cPLA₂ activation, tau hyperphosphorylation, and synaptic loss. Our results support that small molecule inhibitors of cPLA₂ can modulate the downstream inflammatory signaling, offering a promising therapeutic strategy for neurodegenerative diseases.