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1. 发明申请

WO03053921A9 MUTANT PROTEINASE INHIBITORS AND USES THEREOF 审中-公开
标题翻译：突变型蛋白酶抑制剂及其用途
公开(公告)号：WO03053921A9
公开(公告)日：2004-05-13
申请号：PCT/US0222822
申请日：2002-07-18
申请人： AMERICAN NAT RED CROSS , WYETH CORP , LAWRENCE DANIEL A , GORLATOVA NATALIA , CRANDALL DAVID L
发明人： LAWRENCE DANIEL A , GORLATOVA NATALIA , CRANDALL DAVID L
IPC分类号： G01N33/50 , A61K45/00 , A61P43/00 , C07K14/81 , C07K16/38 , C12N1/15 , C12N1/19 , C12N1/21 , C12N5/10 , C12N9/48 , C12N15/09 , C12P21/02 , C12Q1/37 , G01N33/15 , G01N33/53 , G01N33/566 , C07D
CPC分类号： C07K14/8121 , C07K14/81 , C07K14/8132 , C07K16/38 , C12Q1/37 , G01N2333/81 , G01N2500/04
摘要： A library of mutants of metastable proteins, such as proteinase inhibitors, can be screened for the specific loss of a wild-type capability to bind an antibody, yielding valuable drug-design information which otherwise is unavailable. By this approach, for example, a mutant proteinase inhibitor can be obtained that has the amino acid sequence of a wild-type protein, or an active fragment therof, save for the presence of one or more mutations in at least one epitope, thereby altering interaction of the mutant with an anti-proteinase inhibitor antibody.
摘要翻译：可以筛选亚稳态蛋白质突变体的文库，例如蛋白酶抑制剂，以便特异性丧失结合抗体的野生型能力，产生否则不可用的有价值的药物设计信息。通过该方法，例如，可以获得具有野生型蛋白质的氨基酸序列或活性片段的突变蛋白酶抑制剂，除了在至少一个表位中存在一个或多个突变，从而改变突变体与抗蛋白酶抑制剂抗体的相互作用。

2. 发明申请

WO03053921A2 MUTANT PROTEINASE INHIBITORS AND USES THEREOF 审中-公开
标题翻译：突变型蛋白酶抑制剂及其用途
公开(公告)号：WO03053921A2
公开(公告)日：2003-07-03
申请号：PCT/US0222822
申请日：2002-07-18
申请人： AMERICAN NAT RED CROSS , LAWRENCE DANIEL A , GORLATOVA NATALIA , CRANDALL DAVID L
发明人： LAWRENCE DANIEL A , GORLATOVA NATALIA , CRANDALL DAVID L
IPC分类号： G01N33/50 , A61K45/00 , A61P43/00 , C07K14/81 , C07K16/38 , C12N1/15 , C12N1/19 , C12N1/21 , C12N5/10 , C12N9/48 , C12N15/09 , C12P21/02 , C12Q1/37 , G01N33/15 , G01N33/53 , G01N33/566 , C07D
CPC分类号： C07K14/8121 , C07K14/81 , C07K14/8132 , C07K16/38 , C12Q1/37 , G01N2333/81 , G01N2500/04
摘要： A library of mutants of metastable proteins, such as proteinase inhibitors, can be screened for the specific loss of a wild-type capability to bind an antibody, yielding valuable drug-design information which otherwise is unavailable. By this approach, for example, a mutant proteinase inhibitor can be obtained that has the amino acid sequence of a wild-type protein, or an active fragment therof, save for the presence of one or more mutations in at least one epitope, thereby altering interaction of the mutant with an anti-proteinase inhibitor antibody.
摘要翻译：可以筛选亚稳态蛋白质突变体的文库，例如蛋白酶抑制剂，以便特异性丧失结合抗体的野生型能力，产生否则不可用的有价值的药物设计信息。通过该方法，例如，可以获得具有野生型蛋白质的氨基酸序列或活性片段的突变蛋白酶抑制剂，除了在至少一个表位中存在一个或多个突变，从而改变突变体与抗蛋白酶抑制剂抗体的相互作用。

3. 发明申请

WO0040227A3 METHODS FOR TREATING CONDITIONS ASSOCIATED WITH THE ACCUMULATION OF EXCESS EXTRACELLULAR MATRIX 审中-公开
标题翻译：处理与超细胞基质的累积相关条件的方法
公开(公告)号：WO0040227A3
公开(公告)日：2001-01-18
申请号：PCT/US0000179
申请日：2000-01-05
申请人： UNIV UTAH , AMERICAN NAT RED CROSS , NOBLE NANCY A , BORDER WAYNE A , LAWRENCE DANIEL A
发明人： NOBLE NANCY A , BORDER WAYNE A , LAWRENCE DANIEL A
IPC分类号： A61K31/401 , A61K31/4178 , A61K38/14 , A61K38/49 , A61K38/55 , A61K45/06 , A61K31/00 , A61P13/12
CPC分类号： A61K31/573 , A61K31/401 , A61K31/4178 , A61K38/49 , A61K38/556 , A61K45/06 , A61K2300/00
摘要： The present invention is methods and compositions for reducing and preventing the excess accumulation of extracellular matrix in a tissue and/or organ or at a wound site using a combination of agents that inhibit TGF beta , or using agents that inhibit TGF beta in combination with agents that degrade excess accumulated extracellular matrix. The compositions and methods of the invention are used to treat conditions such as fibrotic diseases and scarring that result from excess accumulation of extracellular matrix, impairing tissue or organ function or skin appearance in a suject.
摘要翻译：本发明是使用抑制TGFβ的试剂的组合或使用抑制TGFβ与试剂组合的试剂来减少和预防组织和/或器官或伤口部位过度积累的方法和组合物这会降低过量的细胞外基质。本发明的组合物和方法用于治疗由细胞外基质的过量积累，损伤组织或器官功能或皮肤外观造成的纤维化疾病和瘢痕形成等疾病。

4. 发明申请

WO2004103313A3 METHODS OF REDUCING VASCULAR PERMEABILITY IN TISSUE BY INHIBITION OF TISSUE PLASMINOGEN ACTIVATOR (TPA) AND TPA INHIBITORS USEFUL THEREIN 审中-公开
标题翻译：通过抑制组织培养基激活剂（TPA）和有用的TPA抑制剂减少组织中血管渗透性的方法
公开(公告)号：WO2004103313A3
公开(公告)日：2005-03-17
申请号：PCT/US2004015873
申请日：2004-05-20
申请人： AMERICAN NAT RED CROSS , LAWRENCE DANIEL A , YEPES MANUEL S , STRICKLAND DUDLEY
发明人： LAWRENCE DANIEL A , YEPES MANUEL S , STRICKLAND DUDLEY
IPC分类号： A61K20060101 , A61K39/395 , G01N33/50 , G01N33/53
CPC分类号： G01N33/5088 , G01N2333/9726 , G01N2800/2871
摘要： The present invention is a method of reducing vascular permeability in tissue of a subject comprising inhibiting the activity of serine proteinase tissue-type plasminogen activator (tPA). This tPA activity which increases permeability of the tissue in a subject results in edema in the tissue is separate from tPA's thrombolytic activity. The present invention more specifically relates to administering an amount of a tPA inhibitor sufficient to reduce the vascular permeability increasing activity of tPA in a subject. Useful tPA inhibitors for the present method are neuroserpin, mutant neuroserpin, wild-type PAI- 1, mutant PAI- 1, an antibody that binds to tPA, an antibody that binds to the low-density lipoprotein (LDL) receptor or a low-density lipoprotein (LDL) receptor family antagonist.
摘要翻译：本发明是减少受试者组织中血管通透性的方法，包括抑制丝氨酸蛋白酶组织型纤溶酶原激活物（tPA）的活性。增加受试者中组织渗透性的这种tPA活性导致组织水肿与tPA的溶栓活性分开。本发明更具体地涉及给予一定量的足以降低受试者中tPA的血管通透性增加活性的量的tPA抑制剂。用于本方法的有用的tPA抑制剂是神经丝氨酸蛋白酶抑制剂，突变型神经丝氨酸蛋白酶抑制剂，野生型PAI-1，突变型PAI-1，结合tPA的抗体，结合低密度脂蛋白（LDL）受体的抗体或低密度脂蛋白密度脂蛋白（LDL）受体家族拮抗剂。

5. 发明申请

WO0138560A2 NOVEL DETECTION METHOD FOR A FUNCTIONALLY ACTIVE FORM OF AN ENZYME IN BIOLOGICAL SAMPLES AND A KIT 审中-公开
标题翻译：用于生物样品中酶的功能活性形式的新型检测方法和试剂盒
公开(公告)号：WO0138560A2
公开(公告)日：2001-05-31
申请号：PCT/US0032315
申请日：2000-11-22
申请人： AMERICAN NAT RED CROSS , LAWRENCE DANIEL A , DAY DUANE
发明人： LAWRENCE DANIEL A , DAY DUANE
IPC分类号： C12Q1/37 , C12Q1/56 , G01N33/573 , C12Q1/00
CPC分类号： G01N33/573 , C12Q1/37 , C12Q1/56
摘要： The present method utilizes the capture of the functionally active form of an enzyme that covalently binds or binds with a dissociation constant of 1 x 10 M or less to an enzyme inhibitor or mutant thereof. The present invention is directed to a method for detecting a functionally active form of an enzyme in a biological sample, comprising contacting an enzyme inhibitor or mutant thereof immobilized on a solid substrate with the biological sample, and measuring the binding of the enzyme inhibitor or mutant thereof to the active form of the enzyme by a detectable label, wherein the enzyme inhibitor specifically forms a covalent bond or binds with a dissociation constant of 1 x 10 M or less with the active form of the enzyme. Further, the present invention is directed to an analytical element useful for carrying out the detection of a functionally active form of an enzyme in biological sample, that includes an enzyme inhibitor or mutant thereof immobilized on a solid substrate, wherein the enzyme inhibitor specifically binds or binds with a dissociation constant of 1 x 10 M or less to the active form the enzyme. This analytical element is included in a kit with an analytical reagent conjugated to a detectable label or conjugated to a reactive molecule that generates a detectable label, wherein the reagent specifically binds to the active form of the enzyme that binds to the enzyme inhibitor. Specific enzyme inhibitors or mutants thereof are designed to covalently bind to specific clinically important enzymes. These enzyme inhibitors contain modifications that facilitate binding to a solid support and optionally modifications that affect the binding to a target enzyme or affect the stability of the inhibitor. The method is particularly useful in measuring the presence of enzymes, such as tPA, elastase, cathepsin G and prostate specific antigen. Also disclosed is a method of immobilizing enzyme inhibitors or mutants thereof on a solid substrate yet retaining the property of covantly binding or binding with a dissociation constant of 1 x 10 M or less to a funcitonally active enzyme.
摘要翻译：本发明的方法利用对酶抑制剂或其突变体以1×10 -9 M以下的解离常数共价结合或结合的功能活性形式的捕获。本发明涉及一种用于检测生物样品中酶的功能活性形式的方法，包括使固定在固体基质上的酶抑制剂或突变体与生物样品接触，并测量酶抑制剂或突变体通过可检测的标记物到酶的活性形式，其中酶抑制剂特异性形成共价键或以1×10 -9 M或更小的解离常数与酶的活性形式结合。此外，本发明涉及用于进行生物样品中功能活性形式的酶的检测的分析元件，其包括固定在固体底物上的酶抑制剂或突变体，其中所述酶抑制剂特异性结合或以1×10 -9 M或更小的解离常数与酶的活性形式结合。该分析元件包含在试剂盒中，其中分析试剂与可检测标记物缀合或与产生可检测标记物的反应性分子缀合，其中该试剂特异性结合与酶抑制剂结合的酶的活性形式。特异性酶抑制剂或其突变体被设计为共价结合特定的临床上重要的酶。这些酶抑制剂含有促进结合固体支持物和任选地影响靶酶结合或影响抑制剂稳定性的修饰。该方法特别可用于测量酶的存在，例如tPA，弹性蛋白酶，组织蛋白酶G和前列腺特异性抗原。还公开了一种将酶抑制剂或其突变体固定在固体底物上的方法，但仍保持与1×10 -9 M或更低的解离常数有机结合或结合的功能。

6. 发明申请

WO2008131047A3 PLASMINOGEN ACTIVATOR INHIBITOR-1 INHIBITORS AND METHODS OF USE THEREOF TO MODULATE LIPID METABOLISM 审中-公开
标题翻译： PLASMINOGEN ACTIVATOR INHIBITOR-1 INHIBITORS及其使用方法来调节脂质代谢
公开(公告)号：WO2008131047A3
公开(公告)日：2009-01-08
申请号：PCT/US2008060542
申请日：2008-04-16
申请人： UNIV MICHIGAN , LAWRENCE DANIEL A , STRICKLAND DUDLEY K , CALE JACQUELINE , SU ENMING JOE , EMAL CORY , WARNOCK MARK
发明人： LAWRENCE DANIEL A , STRICKLAND DUDLEY K , CALE JACQUELINE , SU ENMING JOE , EMAL CORY , WARNOCK MARK
IPC分类号： G01N33/92 , C07C69/88 , C07C311/29 , C07H13/08
CPC分类号： C07C311/29 , C07C69/88 , C07C271/22 , C07C2601/14 , C07H13/08 , G01N33/92 , G01N2333/8132 , G01N2500/02
摘要： The invention relates to plasminogen activator- 1 (PAl-1I) inhibitor compounds and uses thereof in the treatment of any disease or condition associated with elevated PAI-1. The invention includes, but is not limited to, the use of such compounds to modulate lipid metabolism and treat conditions associated with elevated PAI-1, cholesterol, or lipid levels.
摘要翻译：本发明涉及纤溶酶原激活物-1（PAI-1I）抑制剂化合物及其用于治疗与PAI-1升高相关的任何疾病或病症的用途。本发明包括但不限于使用这些化合物来调节脂质代谢和治疗与升高的PAI-1，胆固醇或脂质水平相关的病症。

7. 发明申请

WO2009007112A4 THROMBOMODULIN FOR INCREASING REPERFUSION AND PREVENTING BLOOD VESSELS OBSTRUCTION 审中-公开
标题翻译：用于增加血液循环和预防血液容器的THROMBOMODULIN
公开(公告)号：WO2009007112A4
公开(公告)日：2009-06-11
申请号：PCT/EP2008005623
申请日：2008-07-10
申请人： PAION DEUTSCHLAND GMBH , PETERSEN KARL-UWE , BROHMAN HENNING , LAWRENCE DANIEL A
发明人： PETERSEN KARL-UWE , BROHMAN HENNING , LAWRENCE DANIEL A
IPC分类号： A61K38/00 , A61P7/02 , A61P9/10
CPC分类号： A61K38/366
摘要： Use of thrombomodulin for the manufacture of a medicament for stimulating the reperfusion of an ischemic tissue or organ within a patient in the need thereof, in particular a stroke patient.
摘要翻译：血栓调节蛋白用于制造药物的用途，所述药物用于刺激患者需要的缺血组织或器官的再灌注，特别是中风患者。

8. 发明申请

WO2009007112A3 THROMBOMODULIN FOR INCREASING REPERFUSION AND PREVENTING BLOOD VESSELS OBSTRUCTION 审中-公开
标题翻译：用于增加再灌注和预防血容器障碍的血栓素调节蛋白
公开(公告)号：WO2009007112A3
公开(公告)日：2009-04-16
申请号：PCT/EP2008005623
申请日：2008-07-10
申请人： PAION DEUTSCHLAND GMBH , PETERSEN KARL-UWE , BROHMAN HENNING , LAWRENCE DANIEL A
发明人： PETERSEN KARL-UWE , BROHMAN HENNING , LAWRENCE DANIEL A
IPC分类号： A61K38/00 , A61P7/02 , A61P9/10
CPC分类号： A61K38/366
摘要： Use of thrombomodulin for the manufacture of a medicament for stimulating the reperfusion of an ischemic tissue or organ within a patient in the need thereof, in particular a stroke patient.
摘要翻译：使用血栓调节蛋白制造用于刺激有此需要的患者，特别是中风患者的局部缺血组织或器官的再灌注的药物的用途。

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