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A potent and selective small molecule Kir2.1 inhibitor.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2010 Feb 26 [updated 2010 Oct 20].


Inwardly rectifying potassium channels (Kir) have key regulatory roles controlling electrical activity of diverse cell types. For example, Kir2.1 channels are important in cardiac muscle, where genetic and modeling studies suggest that they control resting potential and contribute to the terminal phase of action potential repolarization. Mutations in the Kir2.1 gene lead to cardiac, developmental and other pathologies. One factor that has hindered development of more complete knowledge of the Kir function has been the lack of specific small molecule tools to dissect Kir2 channel function in intact tissues. Thus, the overall goal of the project is to discover an inhibitor of Kir2.1 channels with an IC50 < 1 ┬ÁM and selectivity versus other related ion channels to provide the first Kir2.1 small molecule, in vitro probe. The current small molecule probe, ML133 (CID-781301) can be used for in vitro and electrophysiological studies of Kir2.x functions with sub-micromolar potency at pH 8.5, and without significant inhibition of the closely related inwardly rectifying potassium channel ROMK. ML133 also displays modest selectivity versus hERG and possesses fair ancillary pharmacology against a larger panel of GPCRs, ion channels and transporters. In vivo PK has not yet been performed.

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