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    Rab7 GTPase Inhibitors and Related Methods of Treatment
    6.
    发明申请
    Rab7 GTPase Inhibitors and Related Methods of Treatment 有权
    Rab7 GTPase抑制剂及相关治疗方法

    公开(公告)号：US20140248268A1

    公开(公告)日：2014-09-04

    申请号：US14278468

    申请日：2014-05-15

    申请人： Angela Wandinger-Ness ,  Larry Sklar ,  Jacob Agola ,  Zurab Surviladze ,  Jeffrey Aube ,  Jennifer Golden ,  Chad E. Schroeder ,  Denise S. Simpson

    发明人： Angela Wandinger-Ness ,  Larry Sklar ,  Jacob Agola ,  Zurab Surviladze ,  Jeffrey Aube ,  Jennifer Golden ,  Chad E. Schroeder ,  Denise S. Simpson

    IPC分类号： C07D495/04 ,  A61K45/06 ,  A61K31/381

    CPC分类号： C07D495/04 ,  A61K31/381 ,  A61K45/06

    摘要： This invention relates to compounds and their use as inhibitors or activators of Rab7 GTPase to treat or prevent the onset of Rab 7 GTPase-associated disorders such as neuropathies, cancer, metabolic diseases of bone and lipid storage. The invention is also applicable to infectious diseases where Rab7 is inactivated or its protein-protein interactions are modulated to facilitate intracellular survival of pathogens. The compound described acts as a competitive inhibitor of nucleotide binding and as such also has utility as a scaffold for targeting other small GTPases. In one aspect, methods of treatment of the invention are used to treat or prevent the onset of hereditary sensory neuropathies such as Charcot-Marie-Tooth type 2B disease. Related pharmaceutical compositions, assays, and drug screens are also provided.

    摘要翻译： 本发明涉及化合物及其作为Rab7 GTPase的抑制剂或活化剂的用途，用于治疗或预防Rab 7 GTP酶相关疾病如神经病变，癌症，骨骼和脂质储存代谢疾病的发生。 本发明也适用于Rab7灭活或其蛋白质 - 蛋白质相互作用被调节以促进病原体的细胞内存活的感染性疾病。 所描述的化合物作为核苷酸结合的竞争性抑制剂，因此也可用作靶向其他小GTP酶的支架。 一方面，本发明的治疗方法用于治疗或预防遗传性感觉神经病发作，例如Charcot-Marie-Tooth 2B型疾病。 还提供了相关的药物组合物，测定和药物筛选。

    Synthesis of functionalized octahydro-isoquinolin-1-one-8-carboxamides, octahydro-isoquinolin-1-one-8-carboxylic esters and analogs, and therapeutic methods
    7.
    发明授权
    Synthesis of functionalized octahydro-isoquinolin-1-one-8-carboxamides, octahydro-isoquinolin-1-one-8-carboxylic esters and analogs, and therapeutic methods 有权
    官能化的八氢 - 异喹啉-1-酮-8-甲酰胺，八氢异喹啉-1-酮-8-羧酸酯和类似物的合成和治疗方法

    公开(公告)号：US08735391B2

    公开(公告)日：2014-05-27

    申请号：US12567573

    申请日：2009-09-25

    申请人： Jeffrey Aube ,  Bryan L. Roth ,  Partha Ghosh ,  Kevin J. Frankowski

    发明人： Jeffrey Aube ,  Bryan L. Roth ,  Partha Ghosh ,  Kevin J. Frankowski

    IPC分类号： A61K31/535 ,  A61K31/497 ,  A61K31/4965 ,  A61K31/47

    CPC分类号： C07D217/24 ,  A61K31/472 ,  C07D217/22 ,  C07D401/06 ,  C07D413/06 ,  C07D417/12

    摘要： A functionalized polycyclic compound can have a structure of Formula 1 or salt, prodrug, analog, or derivative thereof, which compound can be prepared by providing a diene; reacting the diene with a dienophile under sufficient conditions for a combined Diels-Alder/acylation reaction so as to provide a polycyclic compound having a carboxylic acid; and coupling the carboxylic acid with an amine-containing compound or a hydroxyl-containing compound so as to form an amide or an ester and producing a compound having a structure of Formula 1. The compound can be used for modulating an opioid receptor, which can be conducted by administering to an opioid receptor a functionalized polycyclic compound as described herein in an effective amount to modulate the functionality of the opioid receptor. Such opioid modulation can provide a biological benefit to a subject.

    摘要翻译： 官能化的多环化合物可以具有式1或其盐，前药，类似物或衍生物的结构，该化合物可以通过提供二烯制备; 使二烯与亲二烯体在足够的条件下进行组合的狄尔斯 - 阿尔德/酰化反应，以提供具有羧酸的多环化合物; 并将羧酸与含胺化合物或含羟基化合物偶联以形成酰胺或酯，并制备具有式1结构的化合物。该化合物可用于调节阿片受体，其可以 通过向阿片样受体施用如本文所述的官能化多环化合物以有效量来调节阿片受体的功能性来进行。 这种阿片样物质调节可以为受试者提供生物学益处。