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    Glucagon/GLP-1 receptor co-agonists
    8.
    发明授权
    Glucagon/GLP-1 receptor co-agonists 有权
    胰高血糖素/ GLP-1受体共激动剂

    公开(公告)号：US08703701B2

    公开(公告)日：2014-04-22

    申请号：US13515977

    申请日：2010-12-09

    申请人： Richard D. DiMarchi

    发明人： Richard D. DiMarchi

    IPC分类号： A61K38/26 ,  A61P3/10

    CPC分类号： C07K14/605 ,  A61K38/00

    摘要： Provided herein are glucagon analogs comprising a modified amino acid sequence of native human glucagon (SEQ ID NO: 2) that exhibit activity at the glucagon receptor, activity at the GLP-1 receptor, or activity at each of the glucagon receptor and the GLP-1 receptor. In some embodiments, the glucagon analog exhibits at least 100% or more of the activity of native glucagon at the glucagon receptor and/or at least 100% or more of the activity of native GLP-1 at the GLP-1 receptor. In some embodiments, the glucagon analog has an EC50 at the GLP-1 receptor which is within 50-fold or less than the EC50 at the glucagon receptor. In some embodiments, the glucagon analog has an EC50 at the GLP-1 receptor which is two- to ten-fold greater than the EC50 at the glucagon receptor. Related conjugates, dimers and multimers, and pharmaceutical compositions, and uses thereof, are further provided.

    摘要翻译： 本文提供的是包含显示胰高血糖素受体活性，GLP-1受体活性或每种胰高血糖素受体和GLP-1受体活性的天然人胰高血糖素（SEQ ID NO：2）的修饰氨基酸序列的胰高血糖素类似物， 1受体。 在一些实施方案中，胰高血糖素类似物在胰高血糖素受体上表现出至少100％或更多的天然胰高血糖素的活性和/或天然GLP-1在GLP-1受体的至少100％或更多的活性。 在一些实施方案中，胰高血糖素类似物在GLP-1受体处具有在胰高血糖素受体的50倍或更小的EC 50内的EC 50。 在一些实施方案中，胰高血糖素类似物具有GLP-1受体的EC 50，其比胰高血糖素受体的EC50大2至10倍。 还提供了相关的缀合物，二聚体和多聚体，以及药物组合物及其用途。

    YL-BASED INSULIN-LIKE GROWTH FACTORS EXHIBITING HIGH ACTIVITY AT THE INSULIN RECEPTOR
    9.
    发明申请
    YL-BASED INSULIN-LIKE GROWTH FACTORS EXHIBITING HIGH ACTIVITY AT THE INSULIN RECEPTOR 审中-公开
    基于YL的胰岛素样生长因子在胰岛素受体中展示高活性

    公开(公告)号：US20110245164A1

    公开(公告)日：2011-10-06

    申请号：US13130960

    申请日：2009-12-18

    申请人： Richard D. DiMarchi ,  Shujiang Cheng ,  Binbin Kou ,  Jie Han

    发明人： Richard D. DiMarchi ,  Shujiang Cheng ,  Binbin Kou ,  Jie Han

    IPC分类号： A61K38/28 ,  C07K14/62 ,  A61K38/30 ,  A61P3/10 ,  C07K14/65

    CPC分类号： C07K14/65 ,  A61K38/00

    摘要： Insulin-like growth factor analogs are disclosed wherein substitution of the IGF native amino acids, at positions corresponding to positions B16 and B17 of native insulin, with tyrosine and leucine, respectively, increases potency of the resulting analog at the insulin receptor by tenfold. Also disclosed are prodrug and depot formulations of the IGF analogs, wherein the IGF analog has been modified by the linkage of a dipeptide to the analog through an amide bond linkage. The prodrug and depot formulations disclosed herein have extended half lives of at least 2 hours, 10 hours, and more typically greater than 2 are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

    摘要翻译： 公开了胰岛素样生长因子类似物，其中分别用酪氨酸和亮氨酸取代天然胰岛素的位置B16和B17处的IGF天然氨基酸将胰岛素受体上得到的类似物的效力增加十倍。 还公开了IGF类似物的前药和贮库制剂，其中IGF类似物已经通过二肽与类似物通过酰胺键连接而被修饰。 本文公开的前药和贮库制剂具有至少2小时，10小时，更典型地大于2的半衰期在生理条件下通过由化学不稳定性驱动的非酶反应而转化为活性形式。

    GLUCAGON ANALOGS EXHIBITING ENHANCED SOLUBILITY AND STABILITY IN PHYSIOLOGICAL pH BUFFERS
    10.
    发明申请
    GLUCAGON ANALOGS EXHIBITING ENHANCED SOLUBILITY AND STABILITY IN PHYSIOLOGICAL pH BUFFERS 有权
    GLUCAGON ANALOGS展示增强的生理pH缓冲液中的溶解性和稳定性

    公开(公告)号：US20110190200A1

    公开(公告)日：2011-08-04

    申请号：US12999284

    申请日：2009-06-16

    申请人： Richard D. DiMarchi ,  David L. Smiley ,  Maria Dimarchi ,  Joseph Chabenne ,  Jonathan Day

    发明人： Richard D. DiMarchi ,  David L. Smiley ,  Maria Dimarchi ,  Joseph Chabenne ,  Jonathan Day

    IPC分类号： A61K38/26 ,  C07K14/605 ,  A61P3/08

    CPC分类号： C07K14/605 ,  A61K38/00

    摘要： Modified glucagon peptides are disclosed having improved solubility and/or half-life while retaining glucagon agonist activity. The glycogen peptides have been modified by substitution of native amino acids with, and/or addition of, charged amino acids to the carboxy terminus of the peptide. The modified glucagon agonists can be further modified by pegylation, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, or both to further enhance the solubility of the glucagon agonist analogs.

    摘要翻译： 公开了具有改善的溶解度和/或半衰期同时保留胰高血糖素激动剂活性的改良的胰高血糖素肽。 糖原肽已经通过用带氨基酸的氨基酸取代天然氨基酸和/或添加到肽的羧基末端而被修饰。 修饰的胰高血糖素激动剂可以通过聚乙二醇化，或加入选自SEQ ID NO：20，SEQ ID NO：21，SEQ ID NO：23或两者的羧基末端肽进一步修饰，以进一步增强溶解度 的胰高血糖素激动剂类似物。