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    • 3. 发明申请
      WO0100665A3 INHIBITORS OF MEMAPSIN 2 AND USE THEREOF 审中-公开
    • INHIBITORS OF MEMAPSIN 2 AND USE THEREOF
    • MEMAPSIN 2的抑制剂及其用途
    • WO0100665A3
    • 2001-09-27
    • PCT/US0017742
    • 2000-06-27
    • OKLAHOMA MED RES FOUND , UNIV ILLINOIS
    • TANG JORDAN J N , HONG LIN , GHOSH ARUN K
    • 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
    • C07K5/1021 , A61K38/00 , A61K39/00 , C07K1/1136 , C07K5/06026 , C07K5/06043 , C07K5/0806 , C07K2299/00 , C12N9/6421 , C12N9/6478 , Y02A90/26 , Y10S514/879
    • 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.
    • 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。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 4. 发明申请
      WO9967254A3 MULTI-DRUG RESISTANT RETROVIRAL PROTEASE INHIBITORS AND USE THEREOF 审中-公开
    • MULTI-DRUG RESISTANT RETROVIRAL PROTEASE INHIBITORS AND USE THEREOF
    • 多种抗药性复性蛋白酶抑制剂及其用途
    • WO9967254A3
    • 2000-02-10
    • PCT/US9914120
    • 1999-06-23
    • US HEALTH , UNIV ILLINOIS , ERICKSON JOHN W , GULNIK SERGEI V , GHOSH ARUN K , HUSSAIN KHAJA A
    • ERICKSON JOHN W , GULNIK SERGEI V , GHOSH ARUN K , HUSSAIN KHAJA A
    • G01N33/15 , A61K31/34 , A61K31/4525 , A61P31/18 , A61P37/04 , A61P43/00 , C07D493/04 , C12Q1/02 , C12Q1/37 , C07D491/04 , C07D495/04
    • A61K31/4525 , A61K31/34 , C07D493/04 , C12Q1/025 , C12Q1/37 , G01N2333/16 , G01N2333/8142
    • 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.
    • 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。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 6. 发明申请
      WO02053594A3 INHIBITORS OF MEMAPSIN 2 AND USE THEREOF 审中-公开
    • INHIBITORS OF MEMAPSIN 2 AND USE THEREOF
    • MEMAPSIN 2的抑制剂及其用途
    • WO02053594A3
    • 2004-01-08
    • PCT/US0150826
    • 2001-12-28
    • OKLAHOMA MED RES FOUND , UNIV ILLINOIS , TANG JORDAN J N , KOELSCH GERALD , GHOSH ARUN K
    • TANG JORDAN J N , KOELSCH GERALD , GHOSH ARUN K
    • A61K38/00 , A61K45/00 , A61P25/28 , A61P43/00 , C07K5/02 , C07K14/81 , C12N9/64 , C12Q1/37 , G01N33/68 , A61K38/55 , C07K5/03
    • C12N9/6478 , A61K38/00 , C07K5/0207 , C07K14/8142 , C07K2299/00 , C12Q1/37 , G01N33/6896
    • 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.
    • 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。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 7. 发明申请
      WO0100665A9 INHIBITORS OF MEMAPSIN 2 AND USE THEREOF 审中-公开
    • INHIBITORS OF MEMAPSIN 2 AND USE THEREOF
    • MEMAPSIN 2的抑制剂及其用途
    • WO0100665A9
    • 2002-07-25
    • PCT/US0017742
    • 2000-06-27
    • OKLAHOMA MED RES FOUND , UNIV ILLINOIS
    • TANG JORDAN J N , HONG LIN , GHOSH ARUN K
    • 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
    • C07K5/1021 , A61K38/00 , A61K39/00 , C07K1/1136 , C07K5/06026 , C07K5/06043 , C07K5/0806 , C07K2299/00 , C12N9/6421 , C12N9/6478 , Y02A90/26 , Y10S514/879
    • 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.
    • 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。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 9. 发明申请
      WO0048466A3 PROTEASE INHIBITORS THAT OVERCOME DRUG RESISTANCE 审中-公开
    • PROTEASE INHIBITORS THAT OVERCOME DRUG RESISTANCE
    • 蛋白酶抑制剂，可以克服药物耐药性
    • WO0048466A3
    • 2000-12-28
    • PCT/US0004215
    • 2000-02-18
    • OKLAHOMA MED RES FOUND , UNIV ILLINOIS
    • TANG JORDAN J N , GHOSH ARUN K
    • C07D307/20 , C07D307/22 , A61K31/351 , A61P31/18
    • C07D307/20
    • HIV protease inhibitors are among the most powerful drugs in suppressing HIV in human patients. However, HIV developed resistance to all protease inhibitor drugs so far marketed or used in clinical trials. HIV generates resistance by mutating its protease. The strains of HIV containing mutant proteases less vulnerable to inhibitor drug are able to replicate better and maintain the infection. No effective principle exists for the design of resistance-proof HIV protease inhibitors (HIVPr). A new inhibitor has been developed based on a new concept for designing resistance invulnerable HIVPr inhibitors. In vitro data have shown that this inhibitor is effective against many known HIVPr mutants resistant to other HIVPr inhibitor drugs. The new concept is, therefore, generally applicable for the design of other resistance invulnerable HIVPr inhibitor drugs.
    • 艾滋病毒蛋白酶抑制剂是抑制人类患者HIV最有效的药物。 然而，HIV对所有迄今为止在市场上销售或用于临床试验的蛋白酶抑制剂药物都产生了抗药性。 HIV通过突变其蛋白酶产生抗性。 含有突变蛋白酶的HIV株不易受抑制剂药物的影响，能够更好地复制并维持感染。 设计耐药性HIV蛋白酶抑制剂（HIVPr）没有有效的原则。 根据设计抗药性HIVPr抑制剂的新概念开发了一种新的抑制剂。 体外数据显示，该抑制剂对许多已知的对其他HIVPr抑制剂药物耐药的HIVPr突变体有效。 因此，这个新概念通常适用于其他抗药性HIVPr抑制剂药物的设计。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
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