The two-pore domain potassium channel, KCNK9 (or TASK-3), is widely expressed in the nervous system and is important to maintaining resting state membrane potential. Using a high throughput screen, a thiotriazole chemotype was identified with preliminary selectivity over KCNH2 (hERG), KCNQ2, KCNJ2 (Kir2.1) and closely related KCNK3 (TASK-1) channels. A subsequent structure-activity relationship study yielded ML308  , a potent inhibitor of KCNK9 in both a thallium influx fluorescent assay (IC50 = 130 nM) and an automated electrophysiology assay (EC50 = 413 nM). Relative to KCNK3, 51-fold and 8-fold selectivities were observed for KCNK9 in the thallium-based and Qpatch assays, respectively. The potency and selectivity profile of ML308  and the supporting analogs derived thereof are useful pharmacological probes for the study of KCNK9 function.

Development of selective chemical inhibitors for the two-pore potassium channel, KCNK9, through a HTS and hit refinement strategy

248th National Meeting (2014)

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