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    GLUCAGON/GLP-1 RECEPTOR CO-AGONISTS
    27.
    发明公开
    GLUCAGON/GLP-1 RECEPTOR CO-AGONISTS 审中-公开
    COAGONISTEN DES GLUCAGON / GLP-1 ReZEPTORS

    公开(公告)号：EP2512503A2

    公开(公告)日：2012-10-24

    申请号：EP10838149.2

    申请日：2010-12-09

    申请人： Indiana University Research and Technology Corporation

    发明人： DIMARCHI, Richard, D.

    IPC分类号： A61K38/26

    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-I receptor, or activity at each of the glucagon recpeotr and the GLP-I 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-I at the GLP-I receptor. In some embodiments, the glucagon analog has an EC50 at the GLP-I 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-I 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受体活性或各胰高血糖素受体和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天然胰高血糖素的至少100％或更高的活性和/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EC 50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。

    GLUCAGON/GLP-1 RECEPTOR CO-AGONISTS
    28.
    发明公开
    GLUCAGON/GLP-1 RECEPTOR CO-AGONISTS 有权
    GLUCAGON / GLP-1受体激动剂

    公开(公告)号：EP2300037A2

    公开(公告)日：2011-03-30

    申请号：EP09767568.0

    申请日：2009-06-16

    申请人： Indiana University Research and Technology Corporation

    发明人： DIMARCHI, Richard, D. ,  SMILEY, David, L. ,  DIMARCHI, Maria ,  CHABENNE, Joseph ,  DAY, Jonathan ,  PATTERSON, James ,  WARD, Brian, C.

    IPC分类号： A61K38/00

    CPC分类号： C07K14/605

    摘要： Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming intramolecular bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP- 1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, acylation, alkylation, substitution of carboxy terminal amino acids, C- terminal truncation, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).

    摘要翻译： 公开了相对于天然胰高血糖素具有增强的胰高血糖素受体效力的修饰的胰高血糖素肽。 通过形成分子内桥或用酰胺基取代末端羧酸进一步修饰胰高血糖素肽产生显示胰高血糖素/ GLP-1受体共激动剂活性的肽。 溶解度和这些高胰高血糖素效价类似物的稳定性可以通过聚乙二醇化，酰化，烷基化，羧基末端氨基酸的取代，C-末端截短，或额外的羧基末端肽的选自多肽的修饰可以进一步提高 由SEQ ID NO：26（GPSSGAPPPS），SEQ ID NO：27（KRNRNNIA）和SEQ ID NO：28（KRNR）组成。

    GLUCAGON ANTAGONISTS
    29.
    发明公开
    GLUCAGON ANTAGONISTS 有权
    高血糖素拮抗剂

    公开(公告)号：EP2217701A2

    公开(公告)日：2010-08-18

    申请号：EP08845852.6

    申请日：2008-10-23

    申请人： Indiana University Research and Technology Corporation

    发明人： DIMARCHI, Richard, D. ,  YANG, Bin

    IPC分类号： C12N15/09 ,  A61K38/00

    CPC分类号： C07K14/605 ,  A61K38/00

    摘要： Glucagon antagonists are provided which comprise amino acid substitutions and/or chemical modifications to glucagon sequence. In one embodiment, the glucagon antagonists comprise a native glucagon peptide that has been modified by the deletion of the first two to five amino acid residues from the N-terminus and (i) an amino acid substitution at position 9 (according to the numbering of native glucagon) or (ii) substitution of the Phe at position 6 (according to the numbering of native glucagon) with phenyl lactic acid (PLA). In another embodiment, the glucagon antagonists comprise the structure A-B-C as described herein, wherein A is PLA, an oxy derivative thereof, or a peptide of 2-6 amino acids in which two consecutive amino acids of the peptide are linked via an ester or ether bond.