3-[[3-[5-[(3-fluoropyridin-4-yl)carbamoyl]-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]benzoyl]amino]benzoic acid | 1426318-17-3

• 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-[[3-[5-[(3-fluoropyridin-4-yl)carbamoyl]-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]benzoyl]amino]benzoic acid
• CAS: 1426318-17-3
• 化学式: C₃₂H₂₉FN₄O₆
• 分子量: 584.604
• InChiKey: GUMXBEFQRBFUKB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.12
• 重原子数：
  43.0
• 可旋转键数：
  8.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  146.72
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  3-[[3-[5-[(3-fluoropyridin-4-yl)carbamoyl]-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]benzoyl]amino]benzoic acid 在 盐酸 、 4-二甲氨基吡啶 、 1-丙基磷酸酐 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 生成 isopropyl 3-{[(2'-(aminomethyl)-5'-{[(3-fluoropyridin-4-yl)amino]carbonyl}biphenyl-3-yl)carbonyl]amino}benzoate hydrochloric acid salt
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

  摘要：

  ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However; systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-Crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.

  DOI：

  10.1021/acs.jmedchem.5b00308
• 作为产物：
  描述：

  3-羧基苯硼酸 在 4-二甲氨基吡啶 、 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 水 、 sodium carbonate 、 1-丙基磷酸酐 、 lithium hydroxide 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 3-[[3-[5-[(3-fluoropyridin-4-yl)carbamoyl]-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]benzoyl]amino]benzoic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

  摘要：

  ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However; systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-Crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.

  DOI：

  10.1021/acs.jmedchem.5b00308

文献信息

• [EN] NOVEL SOFT ROCK INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS ROCK ASSOUPLISSANTS
  申请人：AMAKEM NV

  公开号：WO2013030366A1

  公开（公告）日：2013-03-07

  The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases and ophthalmic diseases.

  本发明涉及新的激酶抑制剂，更具体地说是ROCK抑制剂，包括此类抑制剂的组合物，特别是制药用组合物，以及在治疗和预防疾病中使用此类抑制剂的用途。特别是，本发明涉及新的ROCK抑制剂，包括此类抑制剂的组合物，特别是制药用组合物，以及在治疗和预防疾病中使用此类抑制剂的用途。此外，本发明还涉及治疗方法和使用所述化合物制造药物的方法，用于多种治疗适应症，包括性功能障碍、炎症性疾病和眼科疾病。