Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4532-5. doi: 10.1016/j.bmcl.2012.05.126. Epub 2012 Jun 7.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • K Cl- Cotransporters
  • Molecular Structure
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology
  • Structure-Activity Relationship
  • Symporters / antagonists & inhibitors*
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology


  • Pyridazines
  • Symporters
  • Thiazoles
  • VU0255011