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.