Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe.
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.
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Eric
E
Delpire
Aleksandra
A
Baranczak
Alex G
AG
Waterson
Kwangho
K
Kim
Nathan
N
Kett
Ryan D
RD
Morrison
J Scott
JS
Daniels
C David
CD
Weaver
Craig W
CW
Lindsley
D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D000096922:K Cl- Cotransporters
D011724:Pyridazines; D027981:Symporters; D013844:Thiazoles; D000096922:K Cl- Cotransporters; C577085:VU0255011