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

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

  • J Pharmacol Exp Ther. 2019 Sep;370(3):350-359. doi: 10.1124/jpet.119.257204.
Sujay V Kharade 1,  Juan Vicente Sanchez-Andres 1,  Mark G Fulton 1,  Elaine L Shelton 1,  Anna L Blobaum 1,  Darren W Engers 1,  Christopher S Hofmann 1,  Prasanna K Dadi 1,  Louise Lantier 1,  David A Jacobson 1,  Craig W Lindsley 1,  Jerod S Denton 2
Affiliations

Affiliations

  • 1 Departments of Anesthesiology (S.V.K., J.S.D.) and Pediatrics (E.L.S.), Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, Jaume I University, Castellon de la Plana, Spain (J.V.S.-A.); Departments of Chemistry (M.G.F., C.W.L.), Pharmacology (M.G.F., A.L.B., D.W.E., C.S.H., C.W.L., J.S.D.), and Molecular Physiology and Biophysics (P.K.D., D.A.J.), and Mouse Metabolic Phenotyping Core (L.L.), Vanderbilt University, Nashville, Tennessee; and Vanderbilt Center for Neuroscience Drug Discovery, Franklin, Tennessee (D.W.E., A.L.B., C.W.L.).
  • 2 Departments of Anesthesiology (S.V.K., J.S.D.) and Pediatrics (E.L.S.), Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, Jaume I University, Castellon de la Plana, Spain (J.V.S.-A.); Departments of Chemistry (M.G.F., C.W.L.), Pharmacology (M.G.F., A.L.B., D.W.E., C.S.H., C.W.L., J.S.D.), and Molecular Physiology and Biophysics (P.K.D., D.A.J.), and Mouse Metabolic Phenotyping Core (L.L.), Vanderbilt University, Nashville, Tennessee; and Vanderbilt Center for Neuroscience Drug Discovery, Franklin, Tennessee (D.W.E., A.L.B., C.W.L.) jerod.s.denton@vumc.org.
PMID: 31201216 DOI: 10.1124/jpet.119.257204
Abstract

Glucose-stimulated Insulin secretion from pancreatic β-cells is controlled by ATP-regulated potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP 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 KATP channels. VU0071063 induces hyperpolarization of β-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.

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