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

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Abstract 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.

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