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Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063


Kharade SVSujay V , Sanchez-Andres JVJuan Vicente , Fulton MGMark G , Shelton ELElaine L , Blobaum ALAnna L , Engers DWDarren W , Hofmann CSChristopher S , Dadi PKPrasanna K , Lantier LLouise , Jacobson DADavid A , Lindsley CWCraig W , Denton JSJerod S . The Journal of pharmacology and experimental therapeutics. 2019 06 14; 370(3). 350-359


Glucose-stimulated insulin secretion from pancreatic -cells is controlled by ATP-regulated potassium (K) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The K channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular K channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular K channels. VU0071063 induces hyperpolarization of -cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.