Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy

Dysfunction of voltage-gated sodium channel Nav1.2 causes
various
epileptic disorders, and inhibition of the channel has emerged as
an attractive therapeutic strategy. However, currently available Nav1.2
inhibitors exhibit low potency and limited structural diversity. In
this study, a novel series of pyrimidine-based derivatives with Nav1.2
inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2,
boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration
potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock
test, with ED50 values of 3.2 and 11.1 mg/kg, respectively.
Compound 35 also demonstrated potent antiepileptic activity
in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg.
Overall, compounds 14 and 35 are promising
leads for the development of new small-molecule therapeutics for epilepsy.