3-(((pyridin-4-ylmethyl)amino)methyl)phenol

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(((pyridin-4-ylmethyl)amino)methyl)phenol
• 英文别名: 3-({[(Pyridin-4-yl)methyl]amino}methyl)phenol；3-[(pyridin-4-ylmethylamino)methyl]phenol
• 化学式: C₁₃H₁₄N₂O
• mdl: MFCD11161259
• 分子量: 214.267
• InChiKey: RSXSJMSASXLVOY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.153
• 拓扑面积：
  45.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(((pyridin-4-ylmethyl)amino)methyl)phenol 在 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 36.0h， 生成 N-(3-(4-bromophenethoxy)benzyl)-4-methoxy-N-(pyridin-4-ylmethyl)benzamide
  参考文献：
  名称：

  Development of GLUT4-selective antagonists for multiple myeloma therapy

  摘要：

  Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (MM) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in MM similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.08.029
• 作为产物：
  描述：

  4-甲氨基吡啶 、 间羟基苯甲醛 在 titanium(IV) isopropylate 、 甲醇 、 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 17.0h， 以85%的产率得到3-(((pyridin-4-ylmethyl)amino)methyl)phenol
  参考文献：
  名称：

  [EN] GLUT4 SELECTIVE INHIBITORS FOR CANCER THERAPY
  [FR] INHIBITEURS SÉLECTIFS DE GLUT4 POUR CANCÉROTHÉRAPIE

  摘要：

  这项披露涉及GLUT 4抑制剂及其作为化疗药物的用途。在某些实施例中，这项披露涉及治疗或预防癌症的方法，包括向需要的受试者施用本披露的一种GLUT 4抑制剂的有效量。在某些实施例中，该GLUT 4抑制剂具有Formula（I），前药，衍生物或其盐，其中所述取代基在此报告。在某些实施例中，该GLUT 4抑制剂是N-(3-(4-氟苯氧基)苄基)-2-(4-甲氧基苯基)-N-(吡啶-4-基甲基)乙酰胺或其盐。

  公开号：

  WO2018125968A1

文献信息

• [EN] GLUT4 SELECTIVE INHIBITORS FOR CANCER THERAPY<br/>[FR] INHIBITEURS SÉLECTIFS DE GLUT4 POUR CANCÉROTHÉRAPIE
  申请人：UNIV EMORY

  公开号：WO2018125968A1

  公开（公告）日：2018-07-05

  This disclosure relates to GLUT 4 inhibitors and uses as chemotherapy agents. In certain embodiments, this disclosure relates to methods of treating or preventing cancer comprising administering an effective amount of a GLUT 4 inhibitor disclosed herein to a subject in need thereof. In certain embodiments, the GLUT 4 inhibitor has Formula (I), prodrugs, derivatives, or salts thereof wherein the substituents are reported herein. In certain embodiments, the GLUT 4 inhibitor is N-(3-(4-fluorophenethoxy)benzyl)-2-(4-methoxyphenyl)- N-(pyridin-4-ylmethyl)acetamide or salts thereof.

  这项披露涉及GLUT 4抑制剂及其作为化疗药物的用途。在某些实施例中，这项披露涉及治疗或预防癌症的方法，包括向需要的受试者施用本披露的一种GLUT 4抑制剂的有效量。在某些实施例中，该GLUT 4抑制剂具有Formula（I），前药，衍生物或其盐，其中所述取代基在此报告。在某些实施例中，该GLUT 4抑制剂是N-(3-(4-氟苯氧基)苄基)-2-(4-甲氧基苯基)-N-(吡啶-4-基甲基)乙酰胺或其盐。
• 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS IMMUNOSTIMULANT TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS
  申请人：Bristol-Myers Squibb Company

  公开号：EP3668871B1

  公开（公告）日：2021-08-04
• GLUT4 Selective Inhibitors for Cancer Therapy
  申请人：Emory University

  公开号：US20190321345A1

  公开（公告）日：2019-10-24

  This disclosure relates to GLUT 4 inhibitors and uses as chemotherapy agents. In certain embodiments, this disclosure relates to methods of treating or preventing cancer comprising administering an effective amount of a GLUT 4 inhibitor disclosed herein to a subject in need thereof. In certain embodiments, the GLUT 4 inhibitor has Formula (I), prodrugs, derivatives, or salts thereof wherein the substituents are reported herein. In certain embodiments, the GLUT 4 inhibitor is N-(3-(4-fluorophenethoxy)benzyl)-2-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)acetamide or salts thereof.
• Development of GLUT4-selective antagonists for multiple myeloma therapy
  作者：Changyong Wei、Richa Bajpai、Horrick Sharma、Monique Heitmeier、Atul D. Jain、Shannon M. Matulis、Ajay K. Nooka、Rama K. Mishra、Paul W. Hruz、Gary E. Schiltz、Mala Shanmugam

  DOI：10.1016/j.ejmech.2017.08.029

  日期：2017.10

  Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (MM) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in MM similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics. (C) 2017 Elsevier Masson SAS. All rights reserved.