(((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)diphosphonic acid | 1429012-44-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: (((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)diphosphonic acid
• 英文别名: ({[6-(4-Methylphenyl)thieno[2,3-D]pyrimidin-4-Yl]amino}methanediyl)bis(Phosphonic Acid)；[[[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid
• CAS: 1429012-44-1
• 化学式: C₁₄H₁₅N₃O₆P₂S
• 分子量: 415.303
• InChiKey: SFWLGYOMOJOLFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  181
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  6-溴苯并[2,3-d]嘧啶-4-胺 在 potassium fluoride 、 四(三苯基膦)钯 、 三甲基溴硅烷 作用下， 以 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 0.33h， 生成 (((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)diphosphonic acid
  参考文献：
  名称：

  Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition

  摘要：

  Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.

  DOI：

  10.1021/jm400946f

文献信息

• Discovery of thienopyrimidine-based inhibitors of the human farnesyl pyrophosphate synthase—Parallel synthesis of analogs via a trimethylsilyl ylidene intermediate
  作者：Chun-Yuen Leung、Adrienne M. Langille、John Mancuso、Youla S. Tsantrizos

  DOI：10.1016/j.bmc.2013.02.006

  日期：2013.4

  (hFPPS). Analogs were prepared via cyclization of 2-(1-(trimethylsilyl)ethylidene)malononitrile to 2-amino-4-(trimethylsilyl)thiophene-3-carbonitrile in the presence of elemental sulfur. Direct ipso-iododesilylation of this intermediate led to selective iodination at Cβ of the sulfur atom in high efficiency. The synthetic protocols developed were used in the parallel synthesis of structurally diverse thieno[2

  基于硫代嘧啶的双膦酸酯被鉴定为人法呢基焦磷酸合酶（hFPPS）的一类新型的含氮双膦酸酯（N-BP）抑制剂。在元素硫的存在下，通过将2-（1-（三甲基甲硅烷基）亚乙基）丙二腈环化成2-氨基-4-（三甲基甲硅烷基）噻吩-3-甲腈来制备类似物。引导本位该中间导致了选择性碘化中C的-iododesilylation β在高效率的硫原子的。所开发的合成方案被用于结构平行的hFPPS的基于硫杂[2,3 - d ]嘧啶-4-胺的双膦酸酯抑制剂的合成。
• THIENOPYRIMIDINE INHIBITORS OF FARNESYL AND/OR GERANYLGERANYL PYROPHOSPHATE SYNTHASE
  申请人：THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING/MCGILL UNIVERSITY

  公开号：US20150307532A1

  公开（公告）日：2015-10-29

  The present invention relates to novel compounds, compositions containing same and methods for inhibiting human farnesyl pyrophosphate synthase or for the treatment or prevention of disease conditions using said compounds;

  本发明涉及新型化合物、含有该化合物的组合物以及使用该化合物抑制人类法尼酰二磷酸合酶或治疗或预防疾病的方法。
• Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition
  作者：Chun Yuen Leung、Jaeok Park、Joris W. De Schutter、Michael Sebag、Albert M. Berghuis、Youla S. Tsantrizos

  DOI：10.1021/jm400946f

  日期：2013.10.24

  Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.