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    Gamma-secretase modulatory compounds, methods for identifying same, and uses therefor
    3.
    发明授权
    Gamma-secretase modulatory compounds, methods for identifying same, and uses therefor 有权
    γ-分泌酶调节化合物，鉴定其的方法及其用途

    公开(公告)号：US08871460B2

    公开(公告)日：2014-10-28

    申请号：US13508511

    申请日：2010-11-08

    申请人： Maria Z. Kounnas ,  Elizabeth J. Ackermann ,  Kenneth A. Stauderman ,  Gonul Velicelebi ,  Steve Wagner

    发明人： Maria Z. Kounnas ,  Elizabeth J. Ackermann ,  Kenneth A. Stauderman ,  Gonul Velicelebi ,  Steve Wagner

    IPC分类号： C12Q1/37 ,  G01N33/68

    CPC分类号： G01N33/6896 ,  G01N2500/02

    摘要： In accordance with the present invention, it has been discovered that compounds which modulate the γ-secretase enzyme to make more of the shorter, less toxic and less aggregation-prone Aβ peptides (such as Aβ37 and Aβ38), while making less of the longer and more toxic and aggregation-prone AB peptides (such as AB40 and AB42) are useful as gamma-secretase modulators. In addition, these GSM compounds have further been discovered to have the selective property of modulating the formation of various AB peptides, while not inhibiting the overall activity of the γ-secretase enzyme. Thus, such compounds do not impede other critical functions of the γ-secretase enzyme, such as generating fragments from Notch that appear to control gene expression and cell differentiation. Therefore, in accordance with the present invention, there are provided screening assays useful for determining whether test compounds have GSM activity; accordingly, invention assays facilitate the identification of new gamma-secretase modulators. Such screening assays can be performed in a variety of ways, e.g., by assessing whether test compounds: lower the level of Aβ42 peptide, increase the level of Aβ37 and/or Aβ38 peptides, have substantially no effect on the processing of other γ-secretase substrates, and/or interact with at least one component of the γ-secretase complex. Also provided in accordance with the present invention are compounds having gamma-secretase modulatory activity as identified by any of the methods described herein; methods for producing formulations useful for modulating gamma-secretase activity, as well as the resulting formulations; methods for modulating gamma-secretase activity employing compounds identified according to invention methods and/or invention formulations, and the like.

    摘要翻译： 根据本发明，已经发现调节γ-分泌酶以使更多的较少，较少毒性和较少聚集的A＆Bgr的化合物; 肽（如A＆Bgr 37和A＆bgr 38），同时使较少的较长的和更具毒性和更易聚集的AB肽（如AB40和AB42）可用作γ-分泌酶调节剂。 此外，这些GSM化合物进一步被发现具有调节各种AB肽形成的选择性，而不抑制γ-分泌酶的整体活性。 因此，这些化合物不会阻碍γ-分泌酶的其它关键功能，例如产生似乎控制基因表达和细胞分化的Notch的片段。 因此，根据本发明，提供了用于确定测试化合物是否具有GSM活性的筛选测定法; 因此，本发明分析有助于鉴定新的γ-分泌酶调节剂。 这样的筛选测定可以以多种方式进行，例如，通过评估测试化合物是否降低A＆BGR 42肽的水平，增加A＆bgr 37和/或A＆bgr 38肽的水平对基本上没有影响 处理其他γ-分泌酶底物，和/或与γ-分泌酶复合物的至少一种成分相互作用。 根据本发明还提供了具有通过本文所述的任何方法鉴定的γ-分泌酶调节活性的化合物; 用于制备可用于调节γ-分泌酶活性的制剂的方法，以及所得制剂; 使用根据本发明方法和/或发明制剂鉴定的化合物等来调节γ-分泌酶活性的方法。

    GAMMA-SECRETASE MODULATORY COMPOUNDS, METHODS FOR IDENTIFYING SAME, AND USES THEREFOR
    4.
    发明申请
    GAMMA-SECRETASE MODULATORY COMPOUNDS, METHODS FOR IDENTIFYING SAME, AND USES THEREFOR 有权
    GAMMA-分泌调节剂化合物，其鉴别方法及其用途

    公开(公告)号：US20120289558A1

    公开(公告)日：2012-11-15

    申请号：US13508511

    申请日：2010-11-08

    申请人： Maria Z. Kounnas ,  Elizabeth J. Ackermann ,  Kenneth A. Stauderman ,  Gonul Velicelebi ,  Steve Wagner

    发明人： Maria Z. Kounnas ,  Elizabeth J. Ackermann ,  Kenneth A. Stauderman ,  Gonul Velicelebi ,  Steve Wagner

    IPC分类号： C07D417/10 ,  A61K31/427 ,  G01N27/62 ,  G01N33/573

    CPC分类号： G01N33/6896 ,  G01N2500/02

    摘要： In accordance with the present invention, it has been discovered that compounds which modulate the γ-secretase enzyme to make more of the shorter, less toxic and less aggregation-prone Aβ peptides (such as Aβ37 and Aβ38), while making less of the longer and more toxic and aggregation-prone AB peptides (such as AB40 and AB42) are useful as gamma-secretase modulators. In addition, these GSM compounds have further been discovered to have the selective property of modulating the formation of various AB peptides, while not inhibiting the overall activity of the γ-secretase enzyme. Thus, such compounds do not impede other critical functions of the γ-secretase enzyme, such as generating fragments from Notch that appear to control gene expression and cell differentiation. Therefore, in accordance with the present invention, there are provided screening assays useful for determining whether test compounds have GSM activity; accordingly, invention assays facilitate the identification of new gamma-secretase modulators. Such screening assays can be performed in a variety of ways, e.g., by assessing whether test compounds: lower the level of Aβ42 peptide, increase the level of Aβ37 and/or Aβ38 peptides, have substantially no effect on the processing of other γ-secretase substrates, and/or interact with at least one component of the γ-secretase complex. Also provided in accordance with the present invention are compounds having gamma-secretase modulatory activity as identified by any of the methods described herein; methods for producing formulations useful for modulating gamma-secretase activity, as well as the resulting formulations; methods for modulating gamma-secretase activity employing compounds identified according to invention methods and/or invention formulations, and the like.

    摘要翻译： 根据本发明，已经发现调节γ-分泌酶以使更多的较少，较少毒性和较少聚集的A＆Bgr的化合物; 肽（如A＆Bgr 37和A＆bgr 38），同时使较少的较长的和更具毒性和更易聚集的AB肽（如AB40和AB42）可用作γ-分泌酶调节剂。 此外，这些GSM化合物进一步被发现具有调节各种AB肽形成的选择性，而不抑制γ-分泌酶的整体活性。 因此，这些化合物不会阻碍γ-分泌酶的其它关键功能，例如产生似乎控制基因表达和细胞分化的Notch的片段。 因此，根据本发明，提供了用于确定测试化合物是否具有GSM活性的筛选测定法; 因此，本发明分析有助于鉴定新的γ-分泌酶调节剂。 这样的筛选测定可以以多种方式进行，例如，通过评估测试化合物是否降低A＆BGR 42肽的水平，增加A＆bgr 37和/或A＆bgr 38肽的水平对基本上没有影响 处理其他γ-分泌酶底物，和/或与γ-分泌酶复合物的至少一种成分相互作用。 根据本发明还提供了具有通过本文所述的任何方法鉴定的γ-分泌酶调节活性的化合物; 用于制备可用于调节γ-分泌酶活性的制剂的方法，以及所得制剂; 使用根据本发明方法和/或发明制剂鉴定的化合物等来调节γ-分泌酶活性的方法。