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    Selective maxi-K potassium channel openers functional under conditions of high intracellular calcium concentration, methods and uses thereof
    1.
    发明申请
    Selective maxi-K potassium channel openers functional under conditions of high intracellular calcium concentration, methods and uses thereof 审中-公开
    选择性的maxi-K钾通道开放剂在高细胞内钙浓度的条件下起作用，其方法和用途

    公开(公告)号：US20050043293A1

    公开(公告)日：2005-02-24

    申请号：US10952523

    申请日：2004-09-28

    申请人： Valentin Gribkoff ,  Debra Post-Munson ,  Sarita Yeola ,  Christopher Boissard ,  Piyasena Hewawasam ,  John Starrett

    发明人： Valentin Gribkoff ,  Debra Post-Munson ,  Sarita Yeola ,  Christopher Boissard ,  Piyasena Hewawasam ,  John Starrett

    IPC分类号： G01N33/50 ,  A61K31/40 ,  A61K31/404 ,  A61K45/00 ,  A61P9/10 ,  A61P25/00 ,  A61P25/06 ,  A61P25/08 ,  A61P25/16 ,  A61P25/28 ,  A61P43/00 ,  C07D209/34 ,  G01N27/416 ,  G01N33/15 ,  A61K31/554 ,  A61K31/455 ,  A61K31/549

    CPC分类号： A61K31/40

    摘要： The present invention describes calcium sensitive and selective maxi-K potassium channel opener/activator compounds that function to open maxi-K channels under conditions of high intracellular calcium concentrations, and which do not significantly affect the opening of maxi-K channel proteins under conditions of low or physiologically normal intracellular calcium concentrations. Methods of assaying for and using such compounds are also provided. According to the invention, whole cell voltage patch-clamp studies newly demonstrated that the ability of opener compounds, e.g., fluoro-oxindoles and chloro-oxindoles, to open maxi-K channels was sensitive to the intracellular Ca2+ concentration ([Ca2+])i, i.e., more channels opened at more negative potentials. Particular fluoro-oxindole and chloro-oxindole compounds produced significant increases in whole-cell maxi-K potassium channel-mediated outward currents only in cells having higher [Ca2+]i, compared with effects in lower [Ca2+]i. Such compounds provide Ca2+-sensitive and selective openers of maxi-K channels which show maximum effectiveness under conditions of increased [Ca2+]i and, as such, provide treatments for diseases and disorders in which cells undergo, or are subject to, traumatic stress due to high internal calcium levels, such as stroke.

    摘要翻译： 本发明描述了钙敏感和选择性的max-K钾通道开放剂/活化剂化合物，其在高细胞内钙浓度的条件下起作用以开启max-K通道，并且不显着影响maxi-K通道蛋白在条件 低或生理正常的细胞内钙浓度。 还提供了测定和使用这些化合物的方法。 根据本发明，全细胞电压膜片钳研究新近证明，开放剂化合物（例如氟 - 羟基吲哚和氯 - 羟基吲哚）开放大通道的能力对细胞内Ca 2+浓度敏感（[ Ca 2 +]]）i，即更多的通道在更多的负电位下打开。 特别是氟代羟基吲哚和氯代羟吲哚化合物仅在具有较高[Ca 2+] i的细胞中产生的全细胞最大K钾通道介导的外向电流显着增加，与较低[Ca 2+] ]一世。 这样的化合物提供了在增加[Ca 2+] i的条件下显示出最大有效性的max-K通道的Ca 2+敏感性和选择性开放剂，因此提供细胞经历的疾病和病症的治疗， 或由于内部钙含量高，例如中风而遭受创伤性压力。

    N-substituted prodrugs of fluorooxindoles
    2.
    发明申请
    N-substituted prodrugs of fluorooxindoles 有权
    氟代吲哚的N-取代的前药

    公开(公告)号：US20050203089A1

    公开(公告)日：2005-09-15

    申请号：US11074288

    申请日：2005-03-07

    申请人： John Starrett ,  Omar Lopez ,  Piyasena Hewawasam ,  Min Ding

    发明人： John Starrett ,  Omar Lopez ,  Piyasena Hewawasam ,  Min Ding

    IPC分类号： A61K31/404 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377 ,  C07D413/02

    CPC分类号： C07D209/34 ,  C07D403/12

    摘要： The present invention provides novel N-substituted fluorooxindoles having the general Formula I wherein the wavy bond represents the racemate, the (R)-enantiomer or the (S)-enantiomer and m, n, p, q, A, B, D, Q, X, and Z are as defined below, or a nontoxic pharmaceutically acceptable salt or solvate thereof and are useful in the treatment of disorders which are responsive to the opening of potassium channels.

    摘要翻译： 本发明提供具有通式I的新型N-取代的氟代吲哚，其中波状键表示外消旋物，（R） - 对映体或（S） - 对映体，m，n，p，q，A，B，D， Q，X和Z如下所定义，或其无毒的药学上可接受的盐或溶剂化物，并且可用于治疗对钾通道开放有响应的病症。