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1.发明授权公开(公告)号：US08772318B2
公开(公告)日：2014-07-08
申请号：US12998642
申请日：2009-11-10
IPC分类号： A61K31/443 , C07D405/06
CPC分类号： A61K31/00 , A61K31/496 , C12N15/1137 , C12N2310/14 , C12N2310/531
摘要： This invention provides compounds that selectively inhibit monoacylglycerol lipase (MAGL). The invention also provides methods of using the MAGL selective inhibitors to stimulate 2-Arachidonoylglycerol (2-AG) mediated endocannabinoid signaling in vivo, and to treat conditions that are associated with or linked to endocannabinoid signaling. The invention additionally provides methods of treating cancer or inhibiting tumor growth by targeting MAGL with MAGL specific inhibitors. The invention further provides methods of screening for MAGL inhibitors with improved biochemical and pharmaceutical properties.
摘要翻译： 本发明提供选择性抑制单酰基甘油脂肪酶（MAGL）的化合物。 本发明还提供使用MAGL选择性抑制剂在体内刺激2-花生四烯酰甘油（2-AG）介导的内源性大麻素信号传导的方法，并且治疗与内源性大麻素信号传导相关或连接的病症。 本发明还提供了通过用MAGL特异性抑制剂靶向MAGL来治疗癌症或抑制肿瘤生长的方法。 本发明进一步提供筛选具有改进的生物化学和药物性质的MAGL抑制剂的方法。
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公开(公告)号：US20110275650A1
公开(公告)日：2011-11-10
申请号：US12998642
申请日：2009-11-10
IPC分类号： A61K31/4418 , C07D405/14 , C07D295/155 , A61K31/443 , A61K31/495 , A61P25/00 , A61P29/00 , A61P25/24 , A61P25/22 , A61P9/00 , A61P3/00 , A61P25/28 , A61P27/06 , A61P35/00 , C12N5/09 , C07D213/56
CPC分类号： A61K31/00 , A61K31/496 , C12N15/1137 , C12N2310/14 , C12N2310/531
摘要： This invention provides compounds that selectively inhibit monoacylglycerol lipase (MAGL). The invention also provides methods of using the MAGL selective inhibitors to stimulate 2-Arachidonoylglycerol (2-AG) mediated endocannabinoid signaling in vivo, and to treat conditions that are associated with or linked to endocannabinoid signaling. The invention additionally provides methods of treating cancer or inhibiting tumor growth by targeting MAGL with MAGL specific inhibitors. The invention further provides methods of screening for MAGL inhibitors with improved biochemical and pharmaceutical properties.
摘要翻译： 本发明提供选择性抑制单酰基甘油脂肪酶（MAGL）的化合物。 本发明还提供使用MAGL选择性抑制剂在体内刺激2-花生四烯酰甘油（2-AG）介导的内源性大麻素信号传导的方法，并且治疗与内源性大麻素信号传导相关或连接的病症。 本发明还提供了通过用MAGL特异性抑制剂靶向MAGL来治疗癌症或抑制肿瘤生长的方法。 本发明进一步提供筛选具有改进的生物化学和药物性质的MAGL抑制剂的方法。
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公开(公告)号：US20130164758A1
公开(公告)日：2013-06-27
申请号：US13585298
申请日：2012-08-14
IPC分类号： G01N33/92
CPC分类号： A61K31/325 , C12Q1/34 , G01N33/92 , G01N2500/02
摘要： A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.
摘要翻译： 使用结合基于活性的蛋白质组学和代谢组学的多维分析策略来确定在侵袭性癌细胞中高度升高的先前未表征的酶的活性蛋白质作为桥联血小板激活的醚脂质信号传导网络中的中心节点 因子和溶血磷脂。 生物化学研究证实，活性蛋白通过水解代谢中间体2-乙酰基单烷基甘油来调节该途径。 活性蛋白的失活破坏了癌细胞中的醚类脂质代谢，体内细胞迁移和肿瘤生长受损。
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公开(公告)号：US08940497B2
公开(公告)日：2015-01-27
申请号：US13585298
申请日：2012-08-14
IPC分类号： A61K31/325 , C12Q1/34 , G01N25/02 , G01N33/92
CPC分类号： A61K31/325 , C12Q1/34 , G01N33/92 , G01N2500/02
摘要： A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.
摘要翻译： 使用结合基于活性的蛋白质组学和代谢组学的多维分析策略来确定在侵袭性癌细胞中高度升高的先前未表征的酶的活性蛋白质作为桥联血小板激活的醚脂质信号传导网络中的中心节点 因子和溶血磷脂。 生物化学研究证实，活性蛋白通过水解代谢中间体2-乙酰基单烷基甘油来调节该途径。 活性蛋白的失活破坏了癌细胞中的醚类脂质代谢，体内细胞迁移和肿瘤生长受损。
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公开(公告)号：US20090068107A1
公开(公告)日：2009-03-12
申请号：US11866349
申请日：2007-10-02
CPC分类号： A61K31/325 , C12Q1/34 , G01N33/92 , G01N2500/02
摘要： A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.
摘要翻译： 使用结合基于活性的蛋白质组学和代谢组学的多维分析策略来确定在侵袭性癌细胞中高度升高的先前未表征的酶的活性蛋白质作为桥联血小板激活的醚脂质信号传导网络中的中心节点 因子和溶血磷脂。 生物化学研究证实，活性蛋白通过水解代谢中间体2-乙酰基单烷基甘油来调节该途径。 活性蛋白的失活破坏了癌细胞中的醚类脂质代谢，体内细胞迁移和肿瘤生长受损。
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公开(公告)号：US20080124275A1
公开(公告)日：2008-05-29
申请号：US10534766
申请日：2003-11-14
CPC分类号： C12N9/78 , C07K2299/00
摘要： The present invention is directed to FAAH crystals in complex with the inhibitor methoxyarachidonyl fluorophosphonate (MAFP) and to the use of these crystals to determine the three-dimensional structure of FAAH. This invention id further directed to the use of this structure for the modeling or determination of the structures of related proteins. This invention is further directed to the use of this structure in the pursuit of drug design to identify, characterize, or optimize agents which bind to the active site, substrate channels, product channels, or regulatory sites of FAAH, and to the evaluation of these agents to identify agents which may stimulate, inhibit, relocalize, stabilize, or destabilize FAAH and/or its activity. This invention is further directed to the use of this structure in the development of engineered FAAH variants which display altered solubility, catalytic profiles, or substrate specificity. This invention is further directed to the use of this structure in the development of engineered heterologous proteins with altered membrane tropism.
摘要翻译： 本发明涉及与抑制剂甲氧基花生四烯基氟膦酸酯（MAFP）复合的FAAH晶体以及这些晶体用于确定FAAH的三维结构的用途。 本发明还涉及这种结构用于建模或确定相关蛋白质结构的用途。 本发明进一步涉及这种结构在追求药物设计中以鉴定，表征或优化结合FAAH的活性部位，底物通道，产物通道或调节位点的试剂的用途，以及对这些 用于鉴定可能刺激，抑制，重新定位，稳定或破坏FAAH和/或其活性的药剂的药剂。 本发明进一步涉及这种结构在开发显示改变的溶解度，催化分布或底物特异性的工程FAAH变体中的用途。 本发明进一步涉及这种结构用于开发具有改变的膜向性的工程异源蛋白质的用途。
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7.发明授权Process for antibody combining site-catalyzed SYN elimination in the formation of a CIS olefin 失效用于在形成CIS烯烃中的位点催化的SYN消除的抗体结合方法
公开(公告)号：US5478728A
公开(公告)日：1995-12-26
申请号：US296323
申请日：1994-08-25
IPC分类号： C07C45/65 , C07C205/04 , C07C205/45 , C07C219/24 , C12P5/00 , C12P7/26 , C12P13/00 , C12P21/08 , C12P1/00 , C12N9/00
CPC分类号： C12P13/001 , C07C201/12 , C07C219/24 , C07C221/00 , C07C45/65 , C12P5/026 , C12P7/26 , C07C2102/42
摘要： A process is disclosed by which a substrate is catalytically converted to a cis olefin via a syn elimination reaction. The catalyst is a monoclonal antibody or paratope-containing molecule that binds to the substrate as well as to a bicyclo[2.2.1]heptane or bicylo[2.2.2]octane compound that is an analogue to the substrate having its bulky substituents in eclipsed positions. The chemical reaction is carried out in an aqueous medium. The catalyst molecules and hybridoma cells that secrete those molecules are also contemplated, as is a process for using cyclopentadiene or cyclohexadiene to prepare a hapten used to induce production of the catalyst molecules.
摘要翻译： 公开了一种通过其顺序消除反应将底物催化转化为顺式烯烃的方法。 催化剂是与底物结合的单克隆抗体或辅助聚合物分子，以及与底物相似的双环[2.2.1]庚烷或双环[2.2.2]辛烷化合物，其具有笨重的取代基 职位 化学反应在水性介质中进行。 还考虑分泌这些分子的催化剂分子和杂交瘤细胞，使用环戊二烯或环己二烯制备用于诱导催化剂分子生产的半抗原的方法也是如此。
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公开(公告)号：US07351874B2
公开(公告)日：2008-04-01
申请号：US10209002
申请日：2002-07-30
申请人： Benjamin F. Cravatt
发明人： Benjamin F. Cravatt
IPC分类号： G01N33/00 , A01K67/027
CPC分类号： C12N15/8509 , A01K67/0276 , A01K2217/072 , A01K2217/075 , A01K2227/105 , A01K2267/03 , A01K2267/0356 , A61K49/0008 , C12N9/16 , C12N9/80 , C12N2830/008
摘要： The invention relates to an animal model for studying behavior related to fatty acid amide and hydrolysis of fatty acid amide. The invention provides transgenic animals in which the protein fatty acid amide hydrolase is not expressed, and methods of using such animals.
摘要翻译： 本发明涉及用于研究与脂肪酸酰胺相关的行为和脂肪酸酰胺水解的动物模型。 本发明提供了不表达蛋白质脂肪酸酰胺水解酶的转基因动物，以及使用这些动物的方法。
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公开(公告)号：US07348173B2
公开(公告)日：2008-03-25
申请号：US10788992
申请日：2004-02-26
CPC分类号： C07C45/45 , C07C49/227 , C07C57/03 , C07C233/09 , C07C327/22 , C07F9/5407 , C12N9/80 , C12N9/99 , C12P7/6418
摘要： The soporific activity of cis-9,10-octadecenoamide and other soporific fatty acid primary amides is neutralized by hydrolysis in the presence of fatty-acid amide hydrolase (FAAH). Hydrolysis of cis-9,10-octadecenoamide by FAAH leads to the formation of oleic acid, a compound without soporific activity. FAAH has be isolated and the gene encoding FAAH has been cloned, sequenced, and used to express recombinant FAAH. Inhibitors of FAAH are disclosed to block the hydrolase activity.
摘要翻译： 在脂肪酸酰胺水解酶（FAAH）存在下，通过水解中和顺式-9,10-十八烯酰胺和其它多孔脂肪酸伯酰胺的生物活性。 通过FAAH水解顺式-9,10-十八烯酰胺导致形成油酸，一种没有共同活性的化合物。 FAAH已被分离，编码FAAH的基因已被克隆，测序并用于表达重组FAAH。 公开了FAAH的抑制剂以阻断水解酶活性。
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公开(公告)号：US06251931B1
公开(公告)日：2001-06-26
申请号：US09529909
申请日：2000-04-19
IPC分类号： A61K3140
CPC分类号： C07D295/185 , A61K31/00 , A61K31/16 , A61K31/164 , A61K31/165 , A61K31/17 , A61K31/336 , A61K31/40 , C07C233/05 , C07C233/09 , C07D303/38
摘要： Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and has been shown to effect seratonergic systems and block gap junction communication in a structurally specific manner. Certain agents can serve both as an oleamide agonist and as an inhibitor of fatty acid amide hydrolase. Fatty acid amide hydrolase is responsible for the rapid inactivation of oleamide in vivo. The structural features of oleamide required for inhibition of gap junction-mediated chemical and electrical transmission in rat glial cells are defined. Effective inhibitors fall into two classes of fatty acid primary amides of which oleamide and arachidonamide are the prototypical members. Of these two, oleamide constitutes the most effective and its structural requirements for inhibition of the gap junction are well defined. It requires a chain length of 16-24 carbons of which 16-18 carbons appears optimal, a polarized terminal carbonyl group capable of accepting but not necessarily donating a hydrogen bond, a &Dgr;9 cis double bond, and a hydrophobic methyl terminus. Within these constraints, a range of modifications are possible, many of which may with enhanced in vivo properties.
摘要翻译： 油酰胺是在动物中具有睡眠诱导性质的内源性脂肪酸伯酰胺，并且已经显示出以结构特异性方式影响血清素能系统和阻断间隙连接通信。 某些试剂可用作油酰胺激动剂和作为脂肪酸酰胺水解酶的抑制剂。 脂肪酰胺水解酶负责体内油酰胺的快速灭活。 定义了抑制大鼠神经胶质细胞中间隙连接介导的化学和电传递所需的油酰胺的结构特征。 有效的抑制剂分为两类脂肪酸伯酰胺，其中油酰胺和花生四烯酰胺是原型成员。 在这两种中，油酰胺是最有效的，其对间隙连接的抑制的结构要求是明确的。 它需要16-24个碳原子的链长，其中16-18个碳是最佳的，可以接受但不一定是赋予氢键的极化末端羰基，DELTA9顺式双键和疏水性甲基末端。 在这些约束条件下，一系列修改是可能的，其中许多可能具有增强的体内特性。
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