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    Human G protein-coupled receptor and modulators thereof for the treatment of cardiovascular disorders
    5.
    发明授权
    Human G protein-coupled receptor and modulators thereof for the treatment of cardiovascular disorders 有权
    人G蛋白偶联受体及其调节剂用于治疗心血管疾病

    公开(公告)号：US08017313B2

    公开(公告)日：2011-09-13

    申请号：US10561132

    申请日：2004-06-17

    申请人： John W. Adams ,  Daniel T. Connolly

    发明人： John W. Adams ,  Daniel T. Connolly

    IPC分类号： C12Q1/00 ,  C07K14/705

    CPC分类号： G01N33/74 ,  A01K67/027 ,  A01K67/0275 ,  A01K67/0276 ,  A01K2217/072 ,  A01K2217/075 ,  A01K2227/105 ,  A01K2267/03 ,  C07K14/705 ,  C07K14/723 ,  C07K2319/00 ,  C12N2799/022 ,  G01N33/6893 ,  G01N33/76 ,  G01N2333/726 ,  G01N2800/32 ,  G01N2800/325

    摘要： The present invention relates to methods of identifying whether a candidate compound is a modulator of a G protein-coupled receptor (GPCR). In some embodiments, the GPCR is mammalian, preferably human. In some embodiments, the GPCR is expressed endogenously by cardiomyocytes. In some embodiments, the GPCR is coupled to Gq. In some embodiments, the GPCR increases the intracellular level of inositol 1,4,5-triphosphate (IP3). In some embodiments, a modulator of the GPCR is a modulator of cardiomyocyte hypertrophy. The present invention further relates to methods of using a modulator of the GPCR. Preferred modulators are inverse agonists and antagonists. Inverse agonists and antagonists of the invention are useful as therapeutic agents for the prevention or treatment of heart disease, including hypertrophic cardiomyopathy and congestive heart failure, in particular hypertrophic cardiomyopathy resulting from post-myocardial infarction remodeling, cardiac valve disease, sustained cardiac afterload, myocarditis, and familial hypertrophic cardiomyopathy.

    摘要翻译： 本发明涉及鉴定候选化合物是G蛋白偶联受体（GPCR）的调节剂的方法。 在一些实施方案中，GPCR是哺乳动物，优选人。 在一些实施方案中，GPCR由心肌细胞内源性表达。 在一些实施例中，GPCR耦合到Gq。 在一些实施方案中，GPCR增加1,4,5-三磷酸肌醇（IP3）的细胞内水平。 在一些实施方案中，GPCR的调节剂是心肌细胞肥大的调节剂。 本发明还涉及使用GPCR调制器的方法。 优选的调节剂是反向激动剂和拮抗剂。 本发明的反向激动剂和拮抗剂可用作预防或治疗心脏病，包括肥厚性心肌病和充血性心力衰竭的治疗剂，特别是由心肌梗死后重建，心脏瓣膜疾病，持续的心脏后负荷，心肌炎引起的肥大性心肌病 ，和家族性肥厚型心肌病。

    Human G protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failure
    6.
    发明授权
    Human G protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failure 有权
    人G蛋白偶联受体及其调节剂用于治疗缺血性心脏病和充血性心力衰竭

    公开(公告)号：US07611832B2

    公开(公告)日：2009-11-03

    申请号：US10523100

    申请日：2003-07-25

    申请人： John W. Adams ,  Daniel T. Connolly

    发明人： John W. Adams ,  Daniel T. Connolly

    IPC分类号： C12Q1/00 ,  C07K14/705

    CPC分类号： G01N33/74 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2267/03 ,  C07K14/705 ,  G01N2333/726 ,  G01N2500/04

    摘要： The present invention relates to methods of identifying whether a candidate compound is a modulator of an orphan G protein-coupled receptor (GPCR). Preferably the GPCR is human. In some embodiments, the GPCR is expressed endogenously by cardiomyocytes. In some embodiments, the GPCR is coupled to Gi and lowers the level of intracellular cAMP. In some embodiments, overexpression of the GPCR promotes survival of cardiomyocytes. In some embodiments, overexpression of the GPCR rescues cardiomyoctes from hypoxia/reoxygenation induced apoptosis. In some embodiments, the GPCR is down-regulated in individuals with congestive heart failure. Agonists of the invention are envisioned to be useful as therapeutic agents for the treatment of ischemic heart disease, including myocardial infarction, post-myocardial infarction remodeling, and congestive heart failure.

    摘要翻译： 本发明涉及鉴定候选化合物是否为孤儿G蛋白偶联受体（GPCR）的调节剂的方法。 优选GPCR是人。 在一些实施方案中，GPCR由心肌细胞内源性表达。 在一些实施方案中，GPCR与Gi偶联并降低细胞内cAMP的水平。 在一些实施方案中，GPCR的过表达促进心肌细胞的存活。 在一些实施方案中，GPCR的过表达从心肌缺血/再氧化诱导的细胞凋亡中拯救心肌细胞。 在一些实施方案中，GPCR在具有充血性心力衰竭的个体中下调。 预期本发明的激动剂可用作治疗缺血性心脏病，包括心肌梗死，心肌梗死后重建和充血性心力衰竭的治疗剂。

    Compositions For Treating Flushing And Lipid-Associated Disorders Comprising Niacin Receptor Partial Agonists
    8.
    发明申请
    Compositions For Treating Flushing And Lipid-Associated Disorders Comprising Niacin Receptor Partial Agonists 审中-公开
    用于治疗包含烟酸受体部分激动剂的潮红和脂质相关疾病的组合物

    公开(公告)号：US20080139628A1

    公开(公告)日：2008-06-12

    申请号：US11718539

    申请日：2005-11-01

    申请人： Dominic P. Behan ,  Daniel T. Connolly ,  Jeremy G. Richman

    发明人： Dominic P. Behan ,  Daniel T. Connolly ,  Jeremy G. Richman

    IPC分类号： A61K31/4406 ,  C07D403/04 ,  A61K31/41 ,  A61P3/00 ,  C07D231/14 ,  A61K31/415

    CPC分类号： A61K45/06 ,  A61K31/00 ,  A61K31/415 ,  A61K31/416 ,  A61K31/4162 ,  A61K31/455 ,  A61K2300/00

    摘要： The invention provides a method of reducing flushing induced by niacin or a niacin analog in a subject, comprising administering to said subject an effective flush reducing amount of a niacin receptor partial agonist. In addition, the invention provides a method of reducing flushing induced by niacin or a niacin analog in a subject, comprising administering to said subject an effective flush reducing amount of a niacin receptor partial agonist and an effective lipid altering amount of niacin or a niacin analog. The invention further provides a method of reducing flushing induced by niacin or a niacin analog in a subject, comprising administering to said subject an effective flush reducing amount of a niacin receptor partial agonist and subsequently administering to said subject an effective lipid altering amount of niacin or a niacin analog.

    摘要翻译： 本发明提供了一种减少受试者中烟酸或烟酸类似物引起的潮红的方法，包括向所述受试者施用有效冲洗减少量的烟酸受体部分激动剂。 此外，本发明提供了一种减少受试者中烟酸或烟酸类似物引起的潮红的方法，包括向所述受试者施用有效冲洗减少量的烟酸受体部分激动剂和有效的脂质改变量的烟酸或烟酸类似物 。 本发明进一步提供了一种减少受试者中烟酸或烟酸类似物引起的潮红的方法，包括向所述受试者施用有效冲洗减少量的烟酸受体部分激动剂，随后向所述受试者施用有效的脂质改变量的烟酸或 烟酸类似物。

    Stimulation of endothelial cell growth
    9.
    发明授权
    Stimulation of endothelial cell growth 失效
    刺激内皮细胞生长

    公开(公告)号：US5008196A

    公开(公告)日：1991-04-16

    申请号：US87739

    申请日：1987-08-21

    申请人： Daniel T. Connolly ,  Joseph Feder

    发明人： Daniel T. Connolly ,  Joseph Feder

    IPC分类号： C07K14/52 ,  C12N5/02

    CPC分类号： C07K14/52

    摘要： A method of stimulating endothelial cell growth is provided which comprises subjecting said cells to a growth stimulating amount of a highly purified vascular permeability factor having the following characteristics:(a) it has a M.sub.r about 34,000-40,000 as determined by sodium dodecylsulfate polyacrylamide gel electrophoresis;(b) it is a disulfide-linked protein dimer;(c) it has a N-terminal amino acid sequence as follows: ##STR1## (d) it exhibits substantial mitogenic activity to endothelial cells in culture.

    摘要翻译： 提供刺激内皮细胞生长的方法，其包括使所述细胞经受生长刺激量的具有以下特征的高度纯化的血管通透性因子：（a）通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳测定其具有约34,000-40,000的Mr ; （b）二硫键连接蛋白二聚体; （c）它具有如下的N-末端氨基酸序列：（d）它对培养物中的内皮细胞表现出显着的促有丝分裂活性。

    Methods for Determining Probability of an Adverse or Favorable Reaction to a Niacin Receptor Agonist
    10.
    发明申请
    Methods for Determining Probability of an Adverse or Favorable Reaction to a Niacin Receptor Agonist 审中-公开
    确定烟酸受体激动剂不利或有利反应概率的方法

    公开(公告)号：US20090117559A1

    公开(公告)日：2009-05-07

    申请号：US11990240

    申请日：2006-08-09

    申请人： Chen W. Liaw ,  Martha Kanemitsu-Parks ,  Jeremy G. Richman ,  Dominique Maciejewski-Lenoir ,  Daniel T. Connolly

    发明人： Chen W. Liaw ,  Martha Kanemitsu-Parks ,  Jeremy G. Richman ,  Dominique Maciejewski-Lenoir ,  Daniel T. Connolly

    IPC分类号： C12Q1/68

    CPC分类号： C12Q1/6883 ,  C12Q2600/156 ,  C12Q2600/158

    摘要： The present invention relates generally to a GPR109A niacin receptor. The present invention relates more particularly to assessing a GPR109A polymorphism in an individual, wherein the GPR109A polymorphism is indicative of the subject's risk for an adverse reaction to the administration of a GPR109A receptor agonist, wherein the adverse reaction is associated with stimulation of MAP kinase activity by the GPR109A receptor agonist. More specifically, the present invention relates to assessing a GPR109A polymorphism in an individual and determining the level of risk for the subject for experiencing an adverse reaction, wherein the subject's GPR109A zygosity is predictive of the risk for a cutaneous flushing response that can be experienced following administration of a GPR109A receptor agonist.

    摘要翻译： 本发明一般涉及一种GPR109A烟酸受体。 本发明更具体地涉及评估个体中的GPR109A多态性，其中GPR109A多态性指示受试者对施用GPR109A受体激动剂的不良反应的风险，其中不良反应与MAP激酶活性的刺激相关 由GPR109A受体激动剂。 更具体地，本发明涉及评估个体中的GPR109A多态性并确定受试者经历不良反应的风险水平，其中受试者的GPR109A接合度预示出可能经历的皮肤潮红反应的风险 给予GPR109A受体激动剂。