Development of potent, selective cPLA(2) 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 A(2) (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-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 IC(50) of 0.88 nM in cellular assays that measure cPLA(2)-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 cPLA(2) activation, tau hyperphosphorylation, and synaptic loss. Our results support that small molecule inhibitors of cPLA(2) can modulate the downstream inflammatory signaling, offering a promising therapeutic strategy for neurodegenerative diseases.