methyl 4-methyl-3-(4-phenylpyrimidin-2-ylamino)benzoate | 1093125-16-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl 4-methyl-3-(4-phenylpyrimidin-2-ylamino)benzoate
• 英文别名: methyl 4-methyl-3-[(4-phenylpyrimidin-2-yl)amino]benzoate
• CAS: 1093125-16-6
• 化学式: C₁₉H₁₇N₃O₂
• 分子量: 319.363
• InChiKey: ZDIKKEMYPISIPG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  64.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 4-methyl-3-(4-phenylpyrimidin-2-ylamino)benzoate 在 水 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(2-sulfamoylethyl)phenyl)-3-((4-phenylpyrimidin-2-yl)amino)benzamide
  参考文献：
  名称：

  [EN] HETEROCYCLIC INHIBITORS OF PCSK9
  [FR] INHIBITEURS HÉTÉROCYCLIQUES DE PCSK9

  摘要：

  这种应用涉及可能作为PCSK9的抑制剂或以其他方式调节PCSK9活性的化合物，或其药用可接受的盐、溶剂化合物、前药或多型体，以及包含这些化合物的组合物和配方，以及使用和制备这些化合物的方法。化合物包括式(I)的化合物：(I)其中A、D和Q如本文所述。

  公开号：

  WO2018165718A1
• 作为产物：
  描述：

  4-苯基嘧啶-2-胺 、 3-碘-4-甲基苯甲酸甲酯 在 copper(l) iodide 、 potassium carbonate 、 N,N'-二甲基乙二胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 18.0h， 以39%的产率得到methyl 4-methyl-3-(4-phenylpyrimidin-2-ylamino)benzoate
  参考文献：
  名称：

  [EN] HETEROCYCLIC INHIBITORS OF PCSK9
  [FR] INHIBITEURS HÉTÉROCYCLIQUES DE PCSK9

  摘要：

  这种应用涉及可能作为PCSK9的抑制剂或以其他方式调节PCSK9活性的化合物，或其药用可接受的盐、溶剂化合物、前药或多型体，以及包含这些化合物的组合物和配方，以及使用和制备这些化合物的方法。化合物包括式(I)的化合物：(I)其中A、D和Q如本文所述。

  公开号：

  WO2018165718A1

文献信息

• NOVEL HETEROCYCLE COMPOUNDS AND USES THEREOF
  申请人：Li Peng

  公开号：US20100173924A1

  公开（公告）日：2010-07-08

  The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (I): which penetrate the blood-brain barrier, inhibit the formation and accumulation of beta-amyloid, and are useful in the treatment of neurodegenerative diseases, particularly Alzheimer's disease. Further, the compounds of the present invention inhibit certain kinases, thereby being useful for the treatment of cancers of the central nervous system.

  该发明涉及化学化合物或其药学上可接受的盐，其化学式为(I)：这些化合物可以穿过血脑屏障，抑制β-淀粉样蛋白的形成和积累，并且在神经退行性疾病，特别是阿尔茨海默病的治疗中有用。此外，本发明的化合物可以抑制某些激酶，因此对于中枢神经系统癌症的治疗也有用。
• Heterocycle compounds and uses thereof
  申请人：Li Peng

  公开号：US08367686B2

  公开（公告）日：2013-02-05

  The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (I): which penetrate the blood-brain barrier, inhibit the formation and accumulation of beta-amyloid, and are useful in the treatment of neurodegenerative diseases, particularly Alzheimer's disease. Further, the compounds of the present invention inhibit certain kinases, thereby being useful for the treatment of cancers of the central nervous system.

  该发明涉及化学化合物或其药学上可接受的盐，其化学式为(I)：这些化合物能够穿过血脑屏障，抑制β-淀粉样蛋白的形成和积累，并且在神经退行性疾病，特别是阿尔茨海默病的治疗中有用。此外，本发明的化合物能够抑制某些激酶，因此对于治疗中枢神经系统癌症也有用。
• Heterocyclic inhibitors of PCSK9
  申请人：CARDIO THERAPEUTICS PTY LTD

  公开号：US11091466B2

  公开（公告）日：2021-08-17

  This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, PCSK9, or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof, and to compositions and formulations comprising such compounds, and methods of using and making such compounds. Compounds include comprising of Formula (I): (I) wherein A, D and Q are described herein.

  本申请涉及可作为 PCSK9 抑制剂或以其他方式调节 PCSK9 活性的化合物，或其药学上可接受的盐、溶液剂、原药或多晶型物，还涉及包含此类化合物的组合物和制剂，以及使用和制造此类化合物的方法。化合物包括式（I）：(I) 其中 A、D 和 Q 如本文所述。
• A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove
  作者：Benny J. Evison、James T. Palmer、Gilles Lambert、Herbert Treutlein、Jun Zeng、Brice Nativel、Kévin Chemello、Qing Zhu、Jie Wang、Yanfen Teng、Wei Tang、Yanfeng Xu、Anuj Kumar Rathi、Sanjay Kumar、Alexandra K. Suchowerska、Jasneet Parmar、Ian Dixon、Graham E. Kelly、James Bonnar

  DOI：10.1016/j.bmc.2020.115344

  日期：2020.3

  Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 mu M). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 mu M) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.
• WO2008/153959
  申请人：——

  公开号：——

  公开（公告）日：——