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7-烷基醚类illudalic acid类似物的合成及LAR抑制活性研究(英文) 被引量：1

Synthesis and LAR inhibition of 7-alkoxy analogues of illudalic acid
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摘要 为了获得更强的活性和更好的选择性,基于构效关系合成了一系列7-烷基醚类illudalic acid类似物。这些化合物对人源白细胞共同抗原相关蛋白(LAR)显示亚微摩尔的抑制活性,其中15e的IC50达到180 nmol.L?1。它们是迄今发现的最强效的LAR小分子抑制剂。这些类似物除了对高度同源的PTPσ外,对蛋白酪氨酸磷酸酯酶(PTPs)家族的其他成员均显示出良好的选择性,其中化合物15f对LAR的选择性是对PTP1B抑制活性的120倍。这些强效选择性抑制剂的发现具有重要意义,既可以作为LAR的研究工具同时可能成为II型糖尿病的治疗剂。 To obtain higher potency and specificity,a series of 7-alkoxy analogues of illudalic acid was synthesized on the base of structure-activity relationship（SAR）.All of these compounds exhibited submicromolar inhibition of the enzyme when tested against human leukocyte common antigen-related phosphatase（LAR）（for example,for 15e,IC50 = 180 nmol.L？1）.They represent the most potent small-molecule inhibitors of LAR so far.These analogues also display excellent selectivity for LAR over other protein tyrosine phosphatases（PTPs） except for the highly homologous PTPσ.The compound 15f is of 120-fold selectivity for LAR versus PTP-1B inhibition.The development of potent enzyme-specific inhibitors is so important that they may serve both as tools to study the role of LAR and as therapeutic agents for treatment of type II diabetes.
作者 凌青 周越洋 蔡正良 张亚徽 熊兵 马兰萍 王昕 李欣 李佳 沈竞康
机构地区 中国科学院上海药物研究所新药研究国家重点实验室 国家新药筛选中心
出处 《药学学报》 CAS CSCD 北大核心 2010年第11期1385-1397,共13页 Acta Pharmaceutica Sinica
基金 supported by the Hi-tech Research and Development Program of China through Grant No.2006AA02Z315(L.-P.M)and No.2007AA09Z402(J.L) National Science & Technology Major Project"Key New Drug Creation and Manufacturing Program"of China(No.2009ZX09501-010 and No.2009ZX09301-001).
关键词 人源白细胞共同抗原相关蛋白 illudalic酸 抑制剂 类似物 构效关系 human leukocyte common antigen-related phosphatase illudalic acid inhibitor analogue structure-activity relationship
分类号 R916 [医药卫生—药学]
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参考文献25

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同被引文献11

  • 1Gavalda A, Robetrts RS. Phosphodiesterase-4 inhibitors:a review of current developments (2010-2012)[J]. Expert Opin. Ther. Patents, 2013, 23(8):997-1 016.
  • 2Gaurav A, Singh R. 3D QSAR Pharmacophore, CoMFA and CoMSIA based design and docking studies on phenyl alkyl ke- tones as Inhibitors of phosphodiesterase 4[J]. Med. Chem, 2012, 8(5):894-912.
  • 3Gaurave A, Gautam V, Singh R. Quantitative structure activity relationship and design of phenyl alkyl ketone derivatives as in- hibitors of phosphodiesterase 4 [J]. Current Enzyme Inhibition, 2014, 10(1):69-80.
  • 4Zheng SL, Kaur G, Wang HC, et al. Design, synthesis, and structure-activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors [J]. J Med Chem, 2008, 51(24):7 673-7 688.
  • 5Kojima A, Takita S, Sumiya T, et al. Phosphodiesterase in- hibitors.part 6:design, synthesis,and structure-activity relation- ships of PDE-4-inhibitory pyrazolo[1,5-a]pyridines with anti-in- flammatory activity [J]. Bioorg Med Chem Lett, 2013, 23(19):5 311-5 316.
  • 6Feldig J, Sorensen MD, Poulsen TD, et al. Discovery and early clinical development of 2-{6-[2-(3,5-Dichloro-4-pyridyl)acetyl]- 2,3--dimethoxyphenoxy}-N-propylacetamide (LEO29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis[J]. J Med Chem, 2014, 57(14):5 893-5 903.
  • 7Amschler H. Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors[P]. US:571 229 8,199 501 12.
  • 8Vartanyan SO, Sargsyan AB, Avakyan AS, et al. Synthesis of diamides from 1,4-benzodioxane-2- and isochroman-l-car- boxylic acids[J]. Russ J Org Chem, 2012, 48(7):972-976.
  • 9Day JA, Cohen SM. Investigating the selectivity of metalloenzyme inhibitors[J]. J Med Chem, 2013, 56(20):7 997-8 007.
  • 10陈昌亮,黄爽.磷酸二酯酶及其抑制剂的研究进展[J].中国药理学通报,2014,30(2):283-286. 被引量：26

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药学学报
2010年 第11期

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