Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound , designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. assay showed that exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4, CD8, and CD3 T cells. In the experimental autoimmune encephalomyelitis (EAE) model, showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.