Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe.
AUTHORS
Delpire
EEric ,
Baranczak
A Aleksandra ,
Waterson
AG Alex G ,
Kim
K Kwangho ,
Kett
N Nathan ,
Morrison
RD Ryan D ,
Daniels
JS J Scott ,
Weaver
CD C David ,
Lindsley
CW Craig W .
Bioorganic & medicinal chemistry letters. 2012 7 15; 22(14).
4532-5
- PMID: 22727639[PubMed].
- PMCID: PMC3389279.
- NIHMSID: NIHMS383474
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.