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    Single-chain insulin agonists exhibiting high activity at the insulin receptor
    2.
    发明授权
    Single-chain insulin agonists exhibiting high activity at the insulin receptor 有权
    胰岛素受体表现出高活性的单链胰岛素激动剂

    公开(公告)号：US08940860B2

    公开(公告)日：2015-01-27

    申请号：US13701146

    申请日：2011-06-16

    申请人： Richard D. DiMarchi ,  Julia Azriel ,  Zach Kaur ,  Jonathan Meyers ,  Todd Parody ,  Yan Zhao

    发明人： Richard D. DiMarchi ,  Julia Azriel ,  Zach Kaur ,  Jonathan Meyers ,  Todd Parody ,  Yan Zhao

    IPC分类号： C07K14/62 ,  A61K47/48 ,  A61K38/28 ,  A61K38/00

    CPC分类号： C07K14/62 ,  A61K38/00 ,  A61K38/18 ,  A61K38/28 ,  A61K47/60 ,  C07K14/475

    摘要： Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.

    摘要翻译： 提供具有对胰岛素受体具有高效力和特异性的单链胰岛素类似物。 如本文所公开的，优选尺寸的连接部分可用于连接人胰岛素A和B链或其类似物或衍生物，其中B链的B25氨基酸的羧基末端连接到A1氨基酸的氨基末端 A链通过中间连接部分。 在实施方案中，连接部分包含6-16个单体单元的聚乙二醇，并且在替代实施方案中，连接部分包含衍生自IGF-1 C-肽的非天然氨基酸序列，并且包含至少8个氨基酸且不包含 长度超过12个氨基酸。 还公开了单链胰岛素类似物的前药和缀合物衍生物。

    Glucagon/GLP-1 receptor co-agonists
    4.
    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
    5.
    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
    6.
    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。

    IGF-1 superagonists
    8.
    发明授权
    IGF-1 superagonists 失效
    IGF-1激素

    公开(公告)号：US5622932A

    公开(公告)日：1997-04-22

    申请号：US435252

    申请日：1995-05-05

    申请人： Richard D. DiMarchi ,  Li Fan ,  Harlan B. Long

    发明人： Richard D. DiMarchi ,  Li Fan ,  Harlan B. Long

    IPC分类号： A61K38/27 ,  A61K38/00 ,  A61P43/00 ,  C07K14/575 ,  C07K14/65

    CPC分类号： C07K14/65 ,  A61K38/00

    摘要： The instant invention provides two-chain IGF-1 superagonists which are derivatives of the naturally occurring single-chain IGF-1 having an abbreviated C domain. The invention also provides synthetic and semi-synthetic DNA sequences, recombinant DNA vectors and transformed host cells useful in the recombinant production of these analogs. The invention also provides pharmaceutical formulations comprising these IGF-1 analogs. The invention also provides methods of using these analogs in a variety of therapeutic applications. The instant invention provides IGF-1 analogs of the formula:BC.sup.n,A (1)wherein:B is the B domain of IGF-1 or a functional analog thereof,C is the C domain of IGF-1 or a functional analog thereof,n is the number of amino acids in the C domain and is from about 6 to about 12, andA is the A domain of IGF-1 or a functional analog thereof.

    摘要翻译： 本发明提供了作为具有缩写C结构域的天然存在的单链IGF-1的衍生物的双链IGF-1超激动剂。 本发明还提供用于重组生产这些类似物的合成和半合成DNA序列，重组DNA载体和转化的宿主细胞。 本发明还提供了包含这些IGF-1类似物的药物制剂。 本发明还提供了在各种治疗应用中使用这些类似物的方法。 本发明提供下式的IGF-1类似物：BCn，A（1）其中：B是IGF-1的B结构域或其功能类似物，C是IGF-1的C结构域或其功能类似物， n是C结构域中氨基酸的数目，为约6至约12，A为IGF-1的A结构域或其功能类似物。