NODES_INNDIANA_Z98_Synthesis of SOCE/DHODH Dual Inhibitors: An Innovative Approach for the Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative and immune-mediated disease characterized by inflammation-driven damage to the myelin sheath in the central nervous system. A dysregulated balance between autoreactive and regulatory T cells is a key hallmark of MS pathophysiology and several classes of disease-modifying therapies have been developed to mitigate disease progression. Among these, teriflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, represents a therapeutic option for MS. However, its therapeutic benefits are often offset by significant immunosuppressive adverse effects, underscoring the urgent need for safer and targeted therapeutic strategies. In this context, Store-Operated Calcium Entry (SOCE) mechanism has gained attention as a novel pharmacological target for autoimmune disorders. Its overactivation has been linked to lymphocyte activation and the subsequent release of pro-inflammatory cytokines. Inhibiting SOCE may help mitigate inflammation and prevent neuronal damage, potentially slowing disease progression while maintaining good tolerability and minimizing immunosuppressive side effects. Building on these insights and the promising results obtained with SP20, a dual SOCE/DHODH inhibitor with significant therapeutic potential and excellent in vitro metabolic stability, a structure–activity relationship (SAR) study was conducted with the ultimate goal of discovering novel dual SOCE/DHODH inhibitors as safer alternatives to conventional immunosuppressants.