公开(公告)号：US20130096160A1

公开(公告)日：2013-04-18

申请号：US13641383

申请日：2011-04-14

申请人： Juan Jose Marugan ,  Jingbo Xiao ,  Steven A. Titus ,  Noel Southall ,  Wei Zheng ,  Elliot J. Androphy ,  Jonathan Cherry

发明人： Juan Jose Marugan ,  Jingbo Xiao ,  Steven A. Titus ,  Noel Southall ,  Wei Zheng ,  Elliot J. Androphy ,  Jonathan Cherry

IPC分类号： C07D417/04

CPC分类号： C07D417/04 ,  C07D401/04 ,  C07D405/14 ,  C07D417/14

摘要： Aryl substituted thiazol-2-yl-piperidines and related compounds useful as modulators of survival motor neuron (SMN) protein production are provided herein. Without being bound to any particular theory it is believed the aryl substituted thiazol-2-yl-piperidines and related compounds provided herein act to increase production of the SMN2 form of survival motor neuron protein. These compounds are useful for treating spinal muscular atrophy. Pharmaceutical compositions containing a carrier and one or more of the aryl substituted thiazol-2-yl-piperidine or related compounds described herein are also provided. Methods of treating spinal muscular atrophy are also provided by this disclosure.

摘要翻译： 本文提供了可用作生存运动神经元（SMN）蛋白质生产的调节剂的芳基取代的噻唑-2-基 - 哌啶和相关化合物。 不考虑任何特定理论，据信本文提供的芳基取代的噻唑-2-基 - 哌啶和相关化合物用于增加SMN2形式的存活运动神经元蛋白的产生。 这些化合物可用于治疗脊髓性肌肉萎缩。 还提供了含有本文所述的载体和一种或多种芳基取代的噻唑-2-基 - 哌啶或相关化合物的药物组合物。 本发明还提供了治疗脊髓性肌萎缩症的方法。

公开(公告)号：US20070161573A1

公开(公告)日：2007-07-12

申请号：US11465162

申请日：2006-08-17

申请人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina

发明人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina

IPC分类号： A61K38/06 ,  A61K38/05 ,  A61K31/445

CPC分类号： A61K31/445 ,  A61K47/55 ,  A61K47/64

摘要： Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using specific structural signaling features recognizable by cells as mitochondrial targeting sequences are discussed. A method for delivering these agents effectively into cells and mitochondria where they act as electron scavengers by way of certain targeting sequences is also disclosed. Mitochondria dysfunction and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels.

摘要翻译： 公开了用于治疗由反应氧物质（ROS）的过量线粒体产生引起的与细胞损伤或功能障碍相关的疾病的组合物和方法。 讨论了使用细胞可被线粒体靶向序列识别的特异性结构信号特征作为线粒体选择性靶向剂的组合物。 还公开了一种将这些试剂有效地递送到细胞和线粒体中的方法，其中它们通过某些靶向序列作为电子清除剂。 由于ROS清除活性，线粒体功能障碍和凋亡细胞死亡被抑制，从而增加患者的存活率。 在优选的实施方案中，组合物和方法可以在现场给予具有严重出血性休克的患者的治疗上，使得可以延长存活直到获得出血血管的手术控制。

公开(公告)号：US07718603B1

公开(公告)日：2010-05-18

申请号：US11565779

申请日：2006-12-01

申请人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

发明人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

IPC分类号： A61K38/00

CPC分类号： A61K31/4468 ,  A61K31/555 ,  A61K31/7034 ,  A61K31/7048 ,  A61K47/48023 ,  A61K47/481 ,  A61K47/48246 ,  A61K47/54 ,  A61K47/55 ,  A61K47/64 ,  C07K5/08 ,  C07K5/10 ,  C07K7/06

摘要： The present invention provides a composition and related methods for delivering cargo to a mitochondria which includes (a) a membrane active peptidyl fragment having a high affinity with the mitochondria and (b) cargo. The cargo may be selected from a wide variety of desired cargos which are to be delivered to the mitochondria for a specific purpose. Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using the structural signaling of the β-turn recognizable by cells as mitochondria) targeting sequences are discussed. Mitochondria and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels. In further preferred embodiments, the composition for scavenging radicals in a mitochondria membrane includes a radical scavenging agent and a membrane active compound having a high affinity with said mitochondrial membrane and associated methods. In another embodiment, the cargo transported by mitochondrial-selective targeting agents may include an inhibitor of nitric oxide synthase (NOS) enzyme activity.

摘要翻译： 本发明提供了一种用于将货物运送到线粒体的组合物和相关方法，其包括（a）与线粒体具有高亲和力的膜活性肽基片段和（b）货物。 货物可以选自将被输送到线粒体以用于特定目的的各种期望的货物。 公开了用于治疗由反应氧物质（ROS）的过量线粒体产生引起的与细胞损伤或功能障碍相关的疾病的组合物和方法。 讨论了使用可被细胞作为线粒体识别的靶向序列的结构信号传导作为线粒体选择性靶向剂的组合物。 作为ROS清除活性的结果，线粒体和凋亡细胞死亡被抑制，从而增加患者的存活率。 在优选的实施方案中，组合物和方法可以在现场给予具有严重出血性休克的患者的治疗上，使得可以延长存活直到获得出血血管的手术控制。 在进一步优选的实施方案中，用于清除线粒体膜中的自由基的组合物包括自由基清除剂和与所述线粒体膜具有高亲和力的膜活性化合物和相关方法。 在另一个实施方案中，由线粒体选择性靶向剂运输的货物可以包括一氧化氮合酶（NOS）酶活性的抑制剂。

公开(公告)号：US07528174B2

公开(公告)日：2009-05-05

申请号：US11465162

申请日：2006-08-17

申请人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina

发明人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina

IPC分类号： A61K38/05 ,  A61K38/06 ,  A61K38/08 ,  A61K31/00

CPC分类号： A61K31/445 ,  A61K47/55 ,  A61K47/64

摘要： Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using specific structural signaling features recognizable by cells as mitochondrial targeting sequences are discussed. A method for delivering these agents effectively into cells and mitochondria where they act as electron scavengers by way of certain targeting sequences is also disclosed. Mitochondria dysfunction and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels.

摘要翻译： 公开了用于治疗由反应氧物质（ROS）的过量线粒体产生引起的与细胞损伤或功能障碍相关的疾病的组合物和方法。 讨论了使用细胞可被线粒体靶向序列识别的特异性结构信号特征作为线粒体选择性靶向剂的组合物。 还公开了一种将这些试剂有效地递送到细胞和线粒体中的方法，其中它们通过某些靶向序列作为电子清除剂。 由于ROS清除活性，线粒体功能障碍和凋亡细胞死亡被抑制，从而增加患者的存活率。 在优选的实施方案中，组合物和方法可以在现场给予具有严重出血性休克的患者的治疗上，使得可以延长存活直到获得出血血管的手术控制。

公开(公告)号：US20070161544A1

公开(公告)日：2007-07-12

申请号：US11465524

申请日：2006-08-18

申请人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

发明人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

IPC分类号： A61K38/14 ,  A61K31/7034 ,  A61K31/7048 ,  A61K31/555

CPC分类号： A61K38/446 ,  A61K31/555 ,  A61K31/7034 ,  A61K31/7048 ,  A61K38/08 ,  A61K38/12 ,  A61K47/55 ,  A61K47/64

摘要： The present invention relates to compositions and methods for providing mitochondria-selective targeting agents covalently linked to desired cargo such as radical scavenging agents. Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using specific structural signaling features recognizable by cells as mitochondrial targeting sequences are discussed. A method for delivering these agents effectively into cells and mitochondria where they act as electron scavengers by way of certain targeting sequences is also disclosed. Mitochondria and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels. In further preferred embodiments, the composition for scavenging radicals in a mitochondrial membrane includes a radical scavenging agent and a membrane active compound having a high affinity with said mitochondrial membrane and associated methods. In another embodiment, the cargo transported by mitochondrial-selective targeting agents may include an inhibitor of nitrous oxide system (NOS) enzyme activity.

摘要翻译： 本发明涉及用于提供与期望的货物共价连接的线粒体选择性靶向剂的组合物和方法，例如自由基清除剂。 公开了用于治疗由反应氧物质（ROS）的过量线粒体产生引起的与细胞损伤或功能障碍相关的疾病的组合物和方法。 讨论了使用细胞可被线粒体靶向序列识别的特异性结构信号特征作为线粒体选择性靶向剂的组合物。 还公开了一种将这些试剂有效地递送到细胞和线粒体中的方法，其中它们通过某些靶向序列作为电子清除剂。 作为ROS清除活性的结果，线粒体和凋亡细胞死亡被抑制，从而增加患者的存活率。 在优选的实施方案中，组合物和方法可以在现场给予具有严重出血性休克的患者的治疗上，使得可以延长存活直到获得出血血管的手术控制。 在另外的优选实施方案中，用于清除线粒体膜中的自由基的组合物包括自由基清除剂和与所述线粒体膜具有高亲和力的膜活性化合物和相关方法。 在另一个实施方案中，由线粒体选择性靶向剂运输的货物可以包括一氧化二氮系统（NOS）酶活性的抑制剂。

公开(公告)号：US20110039792A1

公开(公告)日：2011-02-17

申请号：US12750891

申请日：2010-03-31

申请人： Peter Wipf ,  Jingbo Xiao ,  Michell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

发明人： Peter Wipf ,  Jingbo Xiao ,  Michell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

IPC分类号： A61K38/08 ,  C07K5/11 ,  C07K7/06 ,  A61K38/07 ,  C12N5/071

CPC分类号： A61K31/4468 ,  A61K31/555 ,  A61K31/7034 ,  A61K31/7048 ,  A61K47/54 ,  A61K47/55 ,  A61K47/64 ,  C07K5/08 ,  C07K5/10 ,  C07K7/06

摘要： The present invention provides a composition and related methods for delivering cargo to a mitochondria which includes (a) a membrane active peptidyl fragment having a high affinity with the mitochondria and (b) cargo. The cargo may be selected from a wide variety of desired cargos which are to be delivered to the mitochondria for a specific purpose. Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using the structural signaling of the β-turn recognizable by cells as mitochondria) targeting sequences are discussed. Mitochondria and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels. In further preferred embodiments, the composition for scavenging radicals in a mitochondria membrane includes a radical scavenging agent and a membrane active compound having a high affinity with said mitochondrial membrane and associated methods. In another embodiment, the cargo transported by mitochondrial-selective targeting agents may include an inhibitor of nitric oxide synthase (NOS) enzyme activity.

摘要翻译： 本发明提供了一种用于将货物运送到线粒体的组合物和相关方法，其包括（a）与线粒体具有高亲和力的膜活性肽基片段和（b）货物。 货物可以选自将被输送到线粒体以用于特定目的的各种期望的货物。 公开了用于治疗由反应氧物质（ROS）的过量线粒体产生引起的与细胞损伤或功能障碍相关的疾病的组合物和方法。 讨论了使用可被细胞作为线粒体识别的靶向序列的结构信号传导作为线粒体选择性靶向剂的组合物。 作为ROS清除活性的结果，线粒体和凋亡细胞死亡被抑制，从而增加患者的存活率。 在优选的实施方案中，组合物和方法可以在现场给予具有严重出血性休克的患者的治疗上，使得可以延长存活直到获得出血血管的手术控制。 在进一步优选的实施方案中，用于清除线粒体膜中的自由基的组合物包括自由基清除剂和与所述线粒体膜具有高亲和力的膜活性化合物和相关方法。 在另一个实施方案中，由线粒体选择性靶向剂运输的货物可以包括一氧化氮合酶（NOS）酶活性的抑制剂。

公开(公告)号：US20140107317A1

公开(公告)日：2014-04-17

申请号：US14058461

申请日：2013-10-21

申请人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

发明人： Peter Wipf ,  Jingbo Xiao ,  Mitchell P. Fink ,  Valerian E. Kagan ,  Yulia Y. Tyurina ,  Anthony J. Kanai

IPC分类号： C07K5/10 ,  C07K5/08

CPC分类号： A61K31/4468 ,  A61K31/555 ,  A61K31/7034 ,  A61K31/7048 ,  A61K47/48023 ,  A61K47/481 ,  A61K47/48246 ,  A61K47/54 ,  A61K47/55 ,  A61K47/64 ,  C07K5/08 ,  C07K5/10 ,  C07K7/06

摘要： The present invention provides a composition and related methods for delivering cargo to a mitochondria which includes (a) a membrane active peptidyl fragment having a high affinity with the mitochondria and (b) cargo. The cargo may be selected from a wide variety of desired cargoes which are to be delivered to the mitochondria for a specific purpose. Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using the structural signaling of the β-turn recognizable by cells as mitochondria) targeting sequences are discussed. Mitochondria and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient.

摘要翻译： 本发明提供了一种用于将货物运送到线粒体的组合物和相关方法，其包括（a）与线粒体具有高亲和力的膜活性肽基片段和（b）货物。 货物可以选自将要被输送到线粒体用于特定目的的各种期望的货物。 公开了用于治疗由反应氧物质（ROS）的过量线粒体产生引起的与细胞损伤或功能障碍相关的疾病的组合物和方法。 讨论了使用可被细胞作为线粒体识别的靶向序列的结构信号传导作为线粒体选择性靶向剂的组合物。 作为ROS清除活性的结果，线粒体和凋亡细胞死亡被抑制，从而增加患者的存活率。