Discovery of Novel Trisubstituted Pyridine Derivatives as EED-H3K27me3 Inhibitors for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system (CNS) with a significant unmet need for new therapeutic options. Targeting embryonic ectoderm development (EED) is a potential novel therapeutic strategy for treating MS. Herein, based on optimization of potency and pharmacokinetic properties, we report a new class of trisubstituted pyridine derivatives as EED-H3K27me3 inhibitors for MS treatment. Notably, compounds 19 and 21 demonstrate potent EED binding affinity, significantly reduce H3K27me3 levels in dendritic cells (DCs), and effectively inhibit DC migration. Both compounds demonstrate appropriate pharmacokinetic (PK) properties, lymphoid tissue-targeting ability, and favorable in vivo safety profiles. Oral administrations of compounds 19 and 21 dose-dependently reduce spinal cord inflammation and alleviate disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results establish 19 and 21 as promising lead compounds for the development of EED inhibitors for MS therapy.