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

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

Bioorganic & medicinal chemistry letters 2012 Jul 15

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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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Eric Delpire, Aleksandra Baranczak, Alex G Waterson, Kwangho Kim, Nathan Kett, Ryan D Morrison, J Scott Daniels, C David Weaver, Craig W Lindsley. 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(14):4532-5