Kir6.2/SUR1 特异性通道 opener VU0071063 的结构-活性关系、药代动力学和药效学。
Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063.
机构信息
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.).
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.)
出版信息
J Pharmacol Exp Ther. 2019 Sep;370(3):350-359. doi: 10.1124/jpet.119.257204. Epub 2019 Jun 14.
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.
胰腺β细胞的葡萄糖刺激胰岛素分泌受由 Kir6.2 和磺酰脲受体 1 (SUR1) 亚基组成的 ATP 调节钾 (K) 通道控制。K 通道开放剂二氮嗪已获得 FDA 批准用于治疗高胰岛素血症和低血糖症，但存在对血管 K 通道和其他离子通道的非靶向作用。更具特异性的开放剂的开发将为探索 Kir6.2/SUR1 激活的治疗潜力提供急需的工具化合物。在这里，我们描述了我们小组最近在高通量筛选中发现的一种新型 Kir6.2/SUR1 支架激活剂。药物化学的优化工作确定了关键的结构元素，这些元素对于 VU0071063 依赖的 Kir6.2/SUR1 开放是必不可少的。VU0071063 对异源表达的 Kir6.1/SUR2B 通道或动脉导管张力没有影响，表明它不会打开血管 K 通道。VU0071063 诱导β细胞膜电位超极化，并比二氮嗪更有效地抑制胰岛素分泌。VU0071063 表现出有利于体内探针的代谢和药代动力学特性，并且具有脑穿透性。VU0071063 的给药抑制了小鼠的葡萄糖刺激胰岛素分泌和降血糖作用。综上所述，这些研究表明，VU0071063 是一种比二氮嗪更有效和更特异的 Kir6.2/SUR1 开放剂，应该作为研究胰腺和大脑中表达的 Kir6.2/SUR1 的治疗潜力的体外和体内工具化合物有用。
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