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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Structure guided design of a series of sphingosine kinase (SphK) inhibitors
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Structure guided design of a series of sphingosine kinase (SphK) inhibitors

机译：结构引导设计一系列鞘氨酸激酶（SPHK）抑制剂

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摘要

Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.
机译：鞘氨氨酸-1-磷酸（S1P）信号传导在促进剂，细胞迁移和血管生成中起着至关重要的作用。 鞘氨醇激酶（SPHK）催化鞘磷脂代谢的关键步骤，导致S1P的产生。 有两种SPHK同种型和用SPHK缺乏小鼠进行的观察结果显示，两种同种型可以互相补偿彼此的损失。 因此，可能需要对两种同种型的抑制来阻止SPHK依赖性血管生成。 基于结构的方法用于设计和合成一系列SPHK抑制剂，导致鉴定人SPHK两种同种型的第一强抑制剂。 此外，对于我们的知识，这一系列抑制剂含有鼠SPHK1的唯一充分有效的抑制剂，其具有合适的物理化学性质，以药理学地询问SPHK1在啮齿动物模型中的作用，并再现SPHK1（ - / - ）小鼠的表型。

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    GustinD.J.; LiY.; BrownM.L.; MinX.; SchmittM.J.; WanskaM.; WangX.; ConnorsR.; JohnstoneS.; CardozoM.; ChengA.C.; JeffriesS.; FranksB.; LiS.; ShenS.; WongM.; WescheH.; XuG.; CarlsonT.J.; PlantM.; MorgensternK.; RexK.; SchmittJ.; CoxonA.; WalkerN.; KayserF.; WangZ.;

  • 作者单位

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Molecular Structure and Characterization Amgen Inc. 1120 Veterans Boulevard South;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Molecular Structure and Characterization Amgen Inc. 1120 Veterans Boulevard South;

    Department of Molecular Structure and Characterization Amgen Inc. 1120 Veterans Boulevard South;

    Department of Molecular Structure and Characterization Amgen Inc. 1120 Veterans Boulevard South;

    Department of Oncology Research Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080;

    Department of Oncology Research Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080;

    Department of Oncology Research Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080;

    Department of Oncology Research Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080;

    Department of Oncology Research Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080;

    Department of Oncology Research Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080;

    Department of Pharmacokinetics and Drug Metabolism Amgen Inc. 1120 Veterans Boulevard South San;

    Department of Pharmacokinetics and Drug Metabolism Amgen Inc. 1120 Veterans Boulevard South San;

    Department of Lead Discovery Amgen Inc 360 Binney Street Cambridge MA 02041 United States;

    Department of Lead Discovery Amgen Inc 360 Binney Street Cambridge MA 02041 United States;

    Department of Oncology Research One Amgen Center Drive Thousand Oaks CA 91320 United States;

    Department of Oncology Research One Amgen Center Drive Thousand Oaks CA 91320 United States;

    Department of Oncology Research One Amgen Center Drive Thousand Oaks CA 91320 United States;

    Department of Molecular Structure and Characterization Amgen Inc. 1120 Veterans Boulevard South;

    Department of Chemistry Amgen Inc. 1120 Veterans Boulevard South San Francisco CA 94080 United;

    Department of Molecular Structure and Characterization Amgen Inc. 1120 Veterans Boulevard South;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Drug design; Murine SphK; Sphingosine kinase 1 inhibitor; Sphingosine kinase 2 inhibitor; Structure based;

    机译：药物设计;小鼠SPHK;鞘氨醇激酶1抑制剂;鞘氨醇激酶2抑制剂;基于结构;

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