Discovery of 2,4-Disubstituted Pyrimidine Derivatives as Novel Kir4.1 Inhibitors with Rapid-Onset Antidepressant Effect

Depression is a major global health threat and necessitates
novel
rapid-acting and safe antidepressants. Targeting astrocytic Kir4.1
in the lateral habenula has been identified as a potential therapy
strategy for depression with rapid-onset effects. Our research aims
to develop novel and potent Kir4.1 inhibitors with good druggability
through structural modification based on the lead compound EHop-016,
resulting in 37 2,4-disubstituted pyrimidine derivatives. Among these,
compound 37 demonstrated potent Kir4.1 inhibitory activity
(IC50 = 0.19 μM), acceptable Kir subtype selectivity,
favorable pharmacokinetic properties, and safety. Notably, compound 37 exhibited rapid-onset antidepressant effects within 1 h
in the novelty-suppressed feeding test at a dosage three times lower
than that of EHop-016. These findings establish 37 as
a potent and selective Kir4.1 inhibitor with rapid antidepressant
efficacy and good druggability, supporting its further development
for depression treatment.