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

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.
Eric Delpire 1,  Aleksandra Baranczak,  Alex G Waterson,  Kwangho Kim,  Nathan Kett,  Ryan D Morrison,  J Scott Daniels,  C David Weaver,  Craig W Lindsley
Affiliations

Affiliation

  • 1 Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
PMID: 22727639 DOI: 10.1016/j.bmcl.2012.05.126
Abstract

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.

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