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, PI3K delta is a high-value target for autoimmune disease, while the investigation of PI3K delta inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3K delta inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3K delta inhibitory activity and selectivity. In vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4(+), CD8(+), and CD3(+) T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3K delta inhibitor and a new vision for MS therapy.