Delpire E, Baranczak A, Waterson AG, Kim K, Kett N, Morrison RD, Daniels JS, Weaver CD, Lindsley CW. Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. Bioorganic & medicinal chemistry letters. 2012 Jul 15;22(22). 4532-5. PMID: 22727639 [PubMed] PMCID: PMC3389279 NIHMSID: NIHMS383474.
Further chemical optimization of the MLSCN/MLPCN probe ML077 (KCC2 IC(50)=537 nM) proved to be challenging as the effort was characterized by steep SAR. However, a multi-dimensional iterative parallel synthesis approach proved productive. Herein we report the discovery and SAR of an improved novel antagonist (VU0463271) of the neuronal-specific potassium-chloride cotransporter 2 (KCC2), with an IC(50) of 61 nM and >100-fold selectivity versus the closely related Na-K-2Cl cotransporter 1 (NKCC1) and no activity in a larger panel of GPCRs, ion channels and transporters.