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1. 发明申请

WO2011057214A2 GAMMA-SECRETASE MODULATORY COMPOUNDS, METHODS FOR IDENTIFYING SAME, AND USES THEREFOR 审中-公开
标题翻译： GAMMA-分泌调节剂化合物，鉴定其的方法及其用途
公开(公告)号：WO2011057214A2
公开(公告)日：2011-05-12
申请号：PCT/US2010/055869
申请日：2010-11-08
申请人： NEUROGENETIC PHARMACEUTICALS, INC. , KOUNNAS, Maria Z. , ACKERMAN, Elizabeth J. , STAUDERMAN, Kenneth A. , VELICELEBI, Gonul , WAGNER, Steve
发明人： KOUNNAS, Maria Z. , ACKERMAN, Elizabeth J. , STAUDERMAN, Kenneth A. , VELICELEBI, Gonul , WAGNER, Steve
IPC分类号： G01N33/53
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-分泌酶以使更短的，更少的毒性和较少的聚集的Aβ肽（例如Aß37和Aß38）的化合物在减少较长时间的情况下并且更有毒和易聚集的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肽的形成的选择性，而不抑制γ-分泌酶的总体活性。因此，这些化合物不会阻碍β-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，本发明分析方法有助于鉴定新的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，通过评价测试化合物是否降低Aβ42肽的水平，增加Aß37和/或Aβ38肽的水平，对其他γ-分泌酶的加工基本上没有影响底物和/或与α-分泌酶复合物的至少一种组分相互作用。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; 用于产生用于调节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。

2. 发明申请

WO2011057214A3 GAMMA-SECRETASE MODULATORY COMPOUNDS, METHODS FOR IDENTIFYING SAME, AND USES THEREFOR 审中-公开
标题翻译： GAMMA-分泌酶调控化合物，识别方法及其用途
公开(公告)号：WO2011057214A3
公开(公告)日：2011-06-30
申请号：PCT/US2010055869
申请日：2010-11-08
申请人： NEUROGENETIC PHARMACEUTICALS INC , KOUNNAS MARIA Z , ACKERMAN ELIZABETH J , STAUDERMAN KENNETH A , VELICELEBI GONUL , WAGNER STEVE
发明人： KOUNNAS MARIA Z , ACKERMAN ELIZABETH J , STAUDERMAN KENNETH A , VELICELEBI GONUL , WAGNER STEVE
IPC分类号： C40B30/06 , G01N33/48
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 ?-secretase enzyme to make more of the shorter, less toxic and less aggregation-prone Aß peptides (such as Aß37 and Aß38), 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 ?-secretase enzyme. Thus, such compounds do not impede other critical functions of the ?-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 Aß42 peptide,increase the level of Aß37 and/or Aß38 peptides, have substantially no effect on the processing of other ?-secretase substrates, and/or interact with at least one component of the ?-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β-分泌酶以制造更多更短，更低毒性和更少聚集倾向的Aβ肽（如Aβ37和Aβ38），同时减少更长时间和更多毒性和易聚集的AB肽（如AB40和AB42）可用作γ-分泌酶调节剂。此外，还发现这些GSM化合物具有调节各种AB肽形成的选择性，同时不抑制β-分泌酶的整体活性。因此，这样的化合物不阻碍β-分泌酶的其他关键功能，例如产生Notch片段，似乎控制基因表达和细胞分化。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，本发明分析有利于鉴定新的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：降低Aβ42肽水平，增加Aβ37和/或Aβ38肽水平，是否对其他γ-分泌酶加工基本没有影响底物，和/或与γ-分泌酶复合物的至少一种组分相互作用。根据本发明还提供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; 生产用于调节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来调节γ-分泌酶活性的方法等。

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