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1. 发明公开

EP1448218A4 BETA-SECRETASE INHIBITORS AND METHODS OF USE 审中-公开
标题翻译： β-分泌酶抑制剂和使用方法
公开(公告)号：EP1448218A4
公开(公告)日：2009-01-14
申请号：EP02793826
申请日：2002-10-23
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS , COMENTIS INC
发明人： GHOSH ARUN K , TANG JORDAN , BILCER GEOFFREY , CHANG WANPIN , HONG LIN , KOELSCH GERALD , LOY JEFF , TURNER ROBERT T III
IPC分类号： A61K38/00 , A61P25/28 , C07D207/16 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D307/14 , C07D307/16 , C07D307/20 , C07D307/93 , C07D493/04 , C07D521/00 , C07K5/03 , C07K7/02 , C07K14/00 , C07K14/47 , C07K5/10 , C07K7/06
CPC分类号： C07D307/93 , C07D207/16 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D231/12 , C07D233/56 , C07D249/08 , C07D307/14 , C07D307/16 , C07D307/20 , C07D493/04

2. 发明专利

AU2008229725A1 Beta-secretase inhibitors and methods of use 未知
公开(公告)号：AU2008229725A1
公开(公告)日：2008-10-30
申请号：AU2008229725
申请日：2008-10-01
申请人： COMENTIS INC , OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： CHANG WAUPIN , TURNER ROBERT T III , TANG JORDAN , KOELSCH GERALD , BILCER GEOFFREY , GHOSH ARUN K , HONG LIU , LOY JEFF
IPC分类号： A61K38/00 , A61K31/00 , A61P25/28 , C07D207/16 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D307/14 , C07D307/16 , C07D307/20 , C07D307/93 , C07D493/04 , C07D521/00 , C07K5/03 , C07K7/02 , C07K14/00 , C07K14/47
摘要： The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease.

3. 发明专利

AU2008229725B2 Beta-secretase inhibitors and methods of use 未知
公开(公告)号：AU2008229725B2
公开(公告)日：2010-12-09
申请号：AU2008229725
申请日：2008-10-01
申请人： COMENTIS INC , OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： CHANG WANPIN , DEVASAMUDRAM THIPPESWAMY , TURNER ROBERT T III , TANG JORDAN , KOELSCH GERALD , BILCER GEOFFREY , GHOSH ARUN K , HONG LIN , LOY JEFF
IPC分类号： A61K38/00 , C07D207/16 , A61K31/00 , A61P25/28 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D307/14 , C07D307/16 , C07D307/20 , C07D307/93 , C07D493/04 , C07D521/00 , C07K5/03 , C07K7/02 , C07K14/00 , C07K14/47
摘要： The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease.

4. 发明专利

AU2002359301B2 Beta-secretase inhibitors and methods of use 未知
公开(公告)号：AU2002359301B2
公开(公告)日：2008-07-03
申请号：AU2002359301
申请日：2002-10-23
申请人： COMENTIS INC , OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： GHOSH ARUN K , TURNER ROBERT T III , BILCER GEOFFREY , DEVASAMUDRAM THIPPESWAMY , KOELSCH GERALD , TANG JORDAN , CHANG WANPIN , LOY JEFF , HONG LIN
IPC分类号： A61K38/00 , A61K31/00 , A61P25/28 , C07D207/16 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D307/14 , C07D307/16 , C07D307/20 , C07D307/93 , C07D493/04 , C07D521/00 , C07K5/03 , C07K7/02 , C07K14/00 , C07K14/47
摘要： The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease.

5. 发明申请

WO02053594A3 INHIBITORS OF MEMAPSIN 2 AND USE THEREOF 审中-公开
标题翻译： MEMAPSIN 2的抑制剂及其用途
公开(公告)号：WO02053594A3
公开(公告)日：2004-01-08
申请号：PCT/US0150826
申请日：2001-12-28
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS , TANG JORDAN J N , KOELSCH GERALD , GHOSH ARUN K
发明人： TANG JORDAN J N , KOELSCH GERALD , GHOSH ARUN K
IPC分类号： A61K38/00 , A61K45/00 , A61P25/28 , A61P43/00 , C07K5/02 , C07K14/81 , C12N9/64 , C12Q1/37 , G01N33/68 , A61K38/55 , C07K5/03
CPC分类号： C12N9/6478 , A61K38/00 , C07K5/0207 , C07K14/8142 , C07K2299/00 , C12Q1/37 , G01N33/6896
摘要： Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined by a method which determines the initial hydrolysis rate of the substrate by using MALDI-TOF/MS. Alternatively, the subsite specificity of mepapsin can be determined by probing a library of inhibitors with memapsin 2 and subsequently detecting the bound memapsin 2 with an antibody raised to memapsin 2 and an alkaline phosphatase conjugated secondary antibody. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of substrate analogues including isoteres at the sites of the critical amino acid residues were developed and the more than seventy substrate analogues were synthetized, among which MMI-005, MMI-012, MMI-017, MMI-018, MMI-025, MMI-026, MMI-037, MMI-039, MMI-040, MMI-066, MMI-070, and MMI-071 have inhibition constants in the range of 1.4-61.4 x 10 M against recombinant pro-memapsin 2. These inhibitors are useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.
摘要翻译：已经开发了用于生产纯化的，催化活性的重组突变蛋白2的方法。已经通过使用MALDI-TOF / MS确定底物的初始水解速率的方法确定了催化活性酶的底物和亚位点特异性。或者，可以通过用突变蛋白2探测抑制剂文库并随后用提出到膜蛋白酶2的抗体和碱性磷酸酶缀合的第二抗体检测结合的突变蛋白2来确定片段蛋白的亚位点特异性。底物和亚位点特异性信息用于设计可抑制memapsin2功能的天然memapsin 2底物的底物类似物。底物类似物基于肽序列，显示与复制蛋白2的天然肽底物相关。底物类似物含有至少一个酰胺键的类似物，其不能被膜蛋白2切割。合成方法开发了包含在关键氨基酸残基位点的同位素的底物类似物，合成了70多个底物类似物，其中MMI-005，MMI-012，MMI-017，MMI-018，MMI-025，MMI-026 MMI-037，MMI-039，MMI-040，MMI-066，MMI-070和MMI-071对重组pro-memapsin2具有在1.4-61.4×10 -9 M范围内的抑制常数。这些抑制剂可用于诊断和治疗和/或预防阿尔茨海默病。

6. 发明申请

WO03039454A8 BETA-SECRETASE INHIBITORS AND METHODS OF USE 审中-公开
标题翻译： BETA-分泌酶抑制剂和使用方法
公开(公告)号：WO03039454A8
公开(公告)日：2003-09-18
申请号：PCT/US0234324
申请日：2002-10-23
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS , GHOSH ARUN K , TANG JORDAN , BILCER GEOFFREY , CHANG WANPIN , HONG LIN , KOELSCH GERALD , LOY JEFF , TURNER III ROBERT T
发明人： GHOSH ARUN K , TANG JORDAN , BILCER GEOFFREY , CHANG WANPIN , HONG LIN , KOELSCH GERALD , LOY JEFF , TURNER III ROBERT T
IPC分类号： A61K38/00 , A61P25/28 , C07D207/16 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D307/14 , C07D307/16 , C07D307/20 , C07D307/93 , C07D493/04 , C07D521/00 , C07K5/03 , C07K7/02 , C07K14/00 , C07K14/47 , C07K5/10 , C07K7/06
CPC分类号： C07D307/93 , C07D207/16 , C07D213/30 , C07D213/40 , C07D215/14 , C07D215/36 , C07D215/54 , C07D231/12 , C07D233/56 , C07D249/08 , C07D307/14 , C07D307/16 , C07D307/20 , C07D493/04
摘要： Compounds inhibit memapsin 2 beta -secretase activity and selectively inhibit memapsin 2 beta -secretase activity relative to memapsin 1 beta -secretase activity. The compounds are employed in methods to inhibit memapsin 2 beta -secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a beta -secretase site of a beta -amyloid precursor protein and to decrease beta -amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.
摘要翻译：化合物抑制memapsin2β-分泌酶活性并相对于memapsin1β-分泌酶活性选择性抑制memapsin2β-分泌酶活性。该化合物用于抑制memapsin2β-分泌酶活性，治疗阿尔茨海默氏病，抑制β-淀粉状蛋白前体蛋白的β-分泌酶位点的水解和降低体外β-淀粉状蛋白的方法样品和哺乳动物。与本发明化合物缔合的蛋白酶2蛋白质结晶。

7. 发明专利

DE60045005D1 INHIBITOREN DES MEMAPSIN 2 UND IHRE VERWENDUNG 未知
公开(公告)号：DE60045005D1
公开(公告)日：2010-11-04
申请号：DE60045005
申请日：2000-06-27
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： TANG JORDAN J , HONG LIN , GHOSH ARUN K , LIN XINLI , KOELSCH GERALD
IPC分类号： C07K14/81 , C12N15/09 , A61K31/164 , A61K38/00 , A61K38/57 , A61K39/00 , A61P25/28 , A61P43/00 , C07C235/06 , C07C237/12 , C07F7/18 , C07K1/113 , C07K5/097 , C07K5/113 , C12N9/50 , C12N9/64 , C12N9/99 , C12Q1/37

8. 发明专利

AT482233T 未知
公开(公告)号：AT482233T
公开(公告)日：2010-10-15
申请号：AT00943236
申请日：2000-06-27
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： TANG JORDAN , HONG LIN , GHOSH ARUN , LIN XINLI , KOELSCH GERALD
IPC分类号： C07K14/81 , C12N15/09 , A61K31/164 , A61K38/00 , A61K38/57 , A61K39/00 , A61P25/28 , A61P43/00 , C07C235/06 , C07C237/12 , C07F7/18 , C07K1/113 , C07K5/097 , C07K5/113 , C12N9/50 , C12N9/64 , C12N9/99 , C12Q1/37
摘要： Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. 1). The inhibition constant of OM99-2 is 1.6×10−9 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bond to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

9. 发明专利

AU2004202058B2 Inhibitors of memapsin 2 and use thereof 未知
公开(公告)号：AU2004202058B2
公开(公告)日：2007-08-23
申请号：AU2004202058
申请日：2004-05-14
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： HONG LIN , KOELSCH GERALD , TANG JORDAN J N , GHOSH ARUN K , LIN XINLI
IPC分类号： C07K14/00

10. 发明专利

AU2002239727C1 Inhibitors of memapsin 2 and use thereof 未知
公开(公告)号：AU2002239727C1
公开(公告)日：2005-12-22
申请号：AU2002239727
申请日：2001-12-28
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： GHOSH ARUN K , TANG JORDAN J N , KOELSCH GERALD
IPC分类号： C07K14/81 , A61K38/00 , A61K38/55 , A61K45/00 , A61P25/28 , A61P43/00 , C07K5/02 , C07K5/03 , C12N9/64 , C12Q1/37 , G01N33/68
摘要： Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed-, The substrate and subsite specificity of the catalytically active enzyme have been determined by a method which determines the initial hydrolysis rate of the substrates by using MALDI-TOF/MS. Alternatively, the subsite specificity of memapsin can be determined by probing a library of inhibitors with memapsin 2 and subsequently detecting the bound memapsin 2 with an antibody raised to memapsin 2 and an alkaline phosphatase conjugated secondary antibody. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the more than seventy substrate analogues were synthesized, among which MMI-005, MMI-012, MMI-017, MMI-018, MMI-025, MMI-026, MMI-037, MMI-039, MMI-040, MMI-066, MMI-070, and MMI-071 have inhibition constants in the range of 1.4-61.4x10-9 M against recombinant pro-memapsin 2. These inhibitors are useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

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