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 <b>19</b> and <b>21</b> 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 <i>in vivo</i> safety profiles. Oral administrations of compounds <b>19</b> and <b>21</b> dose-dependently reduce spinal cord inflammation and alleviate disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results establish <b>19</b> and <b>21</b> as promising lead compounds for the development of EED inhibitors for MS therapy.