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 31, designed via nitrogen bioisosterism, displayed
excellent PI3Kδ 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 PI3Kδ inhibitor and a new
vision for MS therapy.