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1. 发明申请

WO9967254A3 MULTI-DRUG RESISTANT RETROVIRAL PROTEASE INHIBITORS AND USE THEREOF 审中-公开
标题翻译：多种抗药性复性蛋白酶抑制剂及其用途
公开(公告)号：WO9967254A3
公开(公告)日：2000-02-10
申请号：PCT/US9914120
申请日：1999-06-23
申请人： US HEALTH , UNIV ILLINOIS , ERICKSON JOHN W , GULNIK SERGEI V , GHOSH ARUN K , HUSSAIN KHAJA A
发明人： ERICKSON JOHN W , GULNIK SERGEI V , GHOSH ARUN K , HUSSAIN KHAJA A
IPC分类号： G01N33/15 , A61K31/34 , A61K31/4525 , A61P31/18 , A61P37/04 , A61P43/00 , C07D493/04 , C12Q1/02 , C12Q1/37 , C07D491/04 , C07D495/04
CPC分类号： A61K31/4525 , A61K31/34 , C07D493/04 , C12Q1/025 , C12Q1/37 , G01N2333/16 , G01N2333/8142
摘要： The present invention generally provides a retroviral protease-inhibiting compound represented by formula (I), or a pharmaceutically acceptable salt, a prodrug, or an ester thereof, wherein A is a group of formula (II), (III), (IV), or (V); R , R , R , R , or R is H, or an optionally substituted and/or heteroatom-bearing alkyl, alkenyl, alkynyl, or cyclic group; Y and/or Z are CH2, O, S, SO, SO2, amino, amides, carbamates, ureas or thiocarbonyl derivatives thereof, optionally substituted with an alkyl, alkenyl, or alkynyl group; n is from 1 to 5; X is a bond, an optionally substituted methylene or ethylene, an amino, O or S; Q is C(O), C(S), or SO2; m is from 0 to 6; R is OH, =O (keto), NH2, or alkylamino, including esters, amides, and salts thereof; and W is C(O), C(S), S(O), or SO2; wherein the compound inhibits a multidrug-resistant retroviral protease. Optionally, R and R , together the N-W bond of formula (I), comprise a 12- to 18-membered ring. Also provided are pharmaceutical compositions for, and therapeutic methods of, treating a multidrug-resistant retroviral infection in a mammal.
摘要翻译：本发明通常提供由式（I）表示的逆转录病毒蛋白酶抑制化合物或其药学上可接受的盐，前药或酯，其中A为式（II），（III），（IV），，或（V）; R 1，R 2，R 3，R 5或R 6是H，或任选取代的和/或含杂原子的烷基，烯基，炔基或环状基团; Y和/或Z是任选被烷基，烯基或炔基取代的CH 2，O，S，SO，SO 2，氨基，酰胺，氨基甲酸酯，脲或硫代羰基衍生物; n为1〜5; X是一个键，任选取代的亚甲基或亚乙基，氨基，O或S; Q是C（O），C（S）或SO 2; m为0〜6; R 4是OH，= O（酮），NH 2或烷基氨基，包括酯，酰胺和其盐; W为C（O），C（S），S（O）或SO 2; 其中所述化合物抑制多药耐药逆转录病毒蛋白酶。任选地，R 5和R 6一起形成式（I）的N-W键，包含12至18元环。还提供了用于治疗哺乳动物多药耐药逆转录病毒感染的药物组合物和治疗方法。

2. 发明专利

AU2004200629B2 Fitness assay and associated methods 未知
公开(公告)号：AU2004200629B2
公开(公告)日：2007-04-19
申请号：AU2004200629
申请日：2004-02-18
申请人： UNIV ILLINOIS , US HEALTH
发明人： GULNIK SERGEI V , MITSUYA HIROAKI , ERICKSON JOHN W , GHOSH ARUN K
IPC分类号： C12Q1/00

3. 发明专利

AU2004200629A1 Fitness assay and associated methods 未知
公开(公告)号：AU2004200629A1
公开(公告)日：2004-03-11
申请号：AU2004200629
申请日：2004-02-18
申请人： UNIV ILLINOIS , US HEALTH
发明人： GHOSH ARUN K , MITSUYA HIROAKI , GULNIK SERGEI V , ERICKSON JOHN W
IPC分类号： C12Q1/00

4. 发明专利

AU4828199A Multi-drug resistant retroviral protease inhibitors and associated methods 未知
公开(公告)号：AU4828199A
公开(公告)日：2000-01-10
申请号：AU4828199
申请日：1999-06-23
申请人： US HEALTH , UNIV ILLINOIS
发明人： ERICKSON JOHN W , GULNIK SERGEI V , GHOSH ARUN K , HUSSAIN KHAJA A
IPC分类号： G01N33/15 , A61K31/34 , A61K31/4525 , A61P31/18 , A61P37/04 , A61P43/00 , C07D493/04 , C12Q1/02 , C12Q1/37 , C07D493/00

5. 发明专利

AU2007203321A1 Method of treating HIV infections 未知
公开(公告)号：AU2007203321A1
公开(公告)日：2007-08-09
申请号：AU2007203321
申请日：2007-07-17
申请人： US HEALTH , UNIV ILLINOIS
发明人： GHOSH ARUN K , GULNIK SERGEI V , ERICKSON JOHN W , MITSUYA HIROAKI
IPC分类号： C12Q1/00

6. 发明申请

WO0100665A3 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：WO0100665A3
公开(公告)日：2001-09-27
申请号：PCT/US0017742
申请日：2000-06-27
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： TANG JORDAN J N , HONG LIN , GHOSH ARUN K
IPC分类号： C12N15/09 , A61K31/164 , A61K38/00 , A61K39/00 , A61P25/28 , A61P43/00 , C07C235/06 , C07C237/12 , C07K1/113 , C07K5/097 , C07K5/113 , C12N9/50 , C12N9/64 , C12N9/99 , C12Q1/37 , C07K14/81 , A61K38/57
CPC分类号： C07K5/1021 , A61K38/00 , A61K39/00 , C07K1/1136 , C07K5/06026 , C07K5/06043 , C07K5/0806 , C07K2299/00 , C12N9/6421 , C12N9/6478 , Y02A90/26 , Y10S514/879
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 (Figure 1). The inhibition constant of OM99-2 is 1.6 x 10 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound 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.
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。已经确定了催化活性酶的底物和亚位点特异性。底物和亚位点特异性信息用于设计可以抑制膜蛋白2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memapsin 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，该类似物不能被膜蛋白2切割。开发了两个底物类似物合成的关键氨基酸残基位点处的等位基因，底物类似物OMR99- 1和OM99-2。 OM99-2基于由过渡态等排羟基亚乙基取代的Leu-Ala肽键的八肽Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe（SEQ ID NO：28）（图1）。 OM99-2的抑制常数与重组前体蛋白2相比为1.6×10 -9 M。结合该抑制剂的胶原蛋白2的结晶学用于测定蛋白质的三维结构以及蛋白质的重要性各种残留物的结合。本领域技术人员可以使用本信息来设计新的抑制剂，使用市售的有机化学和酶学方面熟悉的软件程序和技术来设计新的抑制剂2，可用于诊断和治疗和/或预防阿尔茨海默病。

7. 发明申请

WO2004033462A3 METHOD OF PREPARING (3R, 3aS, 6aR) -3- HYDROXYHEXAHYDROFURO [2, 3-b] FURAN AND RELATED COMPOUNDS 审中-公开
标题翻译：制备（3R，3aS，6aR）-3-羟基乙酰基呋喃并[2,3-b]呋喃和相关化合物的方法
公开(公告)号：WO2004033462A3
公开(公告)日：2004-09-30
申请号：PCT/US0332029
申请日：2003-10-08
申请人： UNIV ILLINOIS
发明人： GHOSH ARUN K , LESHCHENKO SOFIYA , NOETZEL MARCUS W
IPC分类号： C07D493/04
CPC分类号： C07D493/04
摘要： A method of synthesizing (3R, 3aS, 6aR) -3- hydroxyhexahydrofuro [2, 3-b] furan (I), and related compounds, in high yield and high enantiomeric selectivity is disclosed. Also disclosed is a method of manufacturing (5S) -5-(benzyloxymethyl) -5H-furan-2-one.
摘要翻译：公开了以高产率和高对映体选择性合成（3R，3aS，6aR）-3-羟基六氢呋喃并[2,3-b]呋喃（I）和相关化合物的方法。还公开了制备（5S）-5-（苄氧基甲基）-5H-呋喃-2-酮的方法。

8. 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。

9. 发明申请

WO0100665A9 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：WO0100665A9
公开(公告)日：2002-07-25
申请号：PCT/US0017742
申请日：2000-06-27
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS
发明人： TANG JORDAN J N , HONG LIN , GHOSH ARUN K
IPC分类号： C12N15/09 , A61K31/164 , A61K38/00 , A61K39/00 , A61P25/28 , A61P43/00 , C07C235/06 , C07C237/12 , C07K1/113 , C07K5/097 , C07K5/113 , C12N9/50 , C12N9/64 , C12N9/99 , C12Q1/37 , C07K14/81 , A61K38/57
CPC分类号： C07K5/1021 , A61K38/00 , A61K39/00 , C07K1/1136 , C07K5/06026 , C07K5/06043 , C07K5/0806 , C07K2299/00 , C12N9/6421 , C12N9/6478 , Y02A90/26 , Y10S514/879
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 (Figure 1). The inhibition constant of OM99-2 is 1.6 x 10 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound 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.
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。已经确定了催化活性酶的底物和亚位点特异性。底物和亚位点特异性信息用于设计可以抑制膜蛋白2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memapsin 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，该类似物不能被膜蛋白2切割。开发了两个底物类似物合成的关键氨基酸残基位点处的等位基因，底物类似物OMR99- 1和OM99-2。 OM99-2基于由过渡态等排羟基亚乙基取代的Leu-Ala肽键的八肽Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe（SEQ ID NO：28）（图1）。 OM99-2的抑制常数与重组前体蛋白2相比为1.6×10 -9 M。结合该抑制剂的胶原蛋白2的结晶学用于测定蛋白质的三维结构以及蛋白质的重要性各种残留物的结合。本领域技术人员可以使用本信息来设计新的抑制剂，使用市售的有机化学和酶学方面熟悉的软件程序和技术来设计新的抑制剂2，可用于诊断和治疗和/或预防阿尔茨海默病。

10. 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。

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