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

Autor:	Kharade SV; 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.)., Sanchez-Andres JV; 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.)., Fulton MG; 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.)., Shelton EL; 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.)., Blobaum AL; 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.)., Engers DW; 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.)., Hofmann CS; 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.)., Dadi PK; 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.)., Lantier L; 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.)., Jacobson DA; 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.)., Lindsley CW; 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.)., Denton JS; 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.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Sep; Vol. 370 (3), pp. 350-359. Date of Electronic Publication: 2019 Jun 14.
DOI:	10.1124/jpet.119.257204
Abstrakt:	Glucose-stimulated insulin secretion from pancreatic β -cells is controlled by ATP-regulated potassium (K ATP ) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The K ATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular K ATP 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 ATP 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. (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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