Benzyl prolinate derivatives as novel selective KCC2 blockers

The discovery and optimization of a novel class of selective submicromolar KCC2 blockers is described. Details of synthesis and SAR are given together with ADME properties of selected compounds. A methylsulfone residue on the R1 phenyl group improved the overall general profile of these prolinate derivatives.

The benzyl prolinate 13 has been identified as a potent KCC2 blocker with selectivity versus NKCC1 and favorable ADME properties. It was evaluated in an in vivo model of epilepsy, the audiogenic mouse seizure test.Figure optionsDownload as PowerPoint slide