2-(3-acrylamido-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide

• 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: 2-(3-acrylamido-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide
• 英文别名: N-[5-(1,3-benzodioxole-5-carbonylamino)-2-methylphenyl]-4-(methylamino)-2-[4-methyl-3-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamide
• 化学式: C₃₁H₂₉N₇O₅
• 分子量: 579.615
• InChiKey: AFFAEAYTDPVNHJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  156
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-甲胺基-2-甲硫基-5-嘧啶甲酸乙酯 在 盐酸 、 tin(II) chloride dihdyrate 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 85.0h， 生成 2-(3-acrylamido-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide
  参考文献：
  名称：

  Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chromosome (BMX) Kinase Inhibitor

  摘要：

  BMX is a member of TEC family nonreceptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high selectivity profile (S score(1) = 0.01) against the 468 kinases/mutants in the KINOMEscan evaluation and achieved at least 40-fold selectivity over BTK kinase. Given the fact that BMX mediated signaling pathway is still not fully understood, compound 41 would serve as a useful pharmacological tool to elucidate the detailed mechanism of BMX mediated signaling pathways.

  DOI：

  10.1021/acs.jmedchem.6b01413

文献信息

• [EN] NOVEL BCR-ABL KINASE INHIBITOR<br/>[FR] NOUVEL INHIBITEUR DE KINASE BCR-ABL<br/>[ZH] 一种新型的BCR-ABL激酶抑制剂
  申请人：[en]HEFEI INSTITUTES OF PHYSICAL SCIENCE, CHINESE ACADEMY OF SCIENCES;[zh]中国科学院合肥物质科学研究院

  公开号：WO2016165205A1

  公开（公告）日：2016-10-20

  本发明公开了一种BCR-ABL激酶抑制剂，其包括式I的化合物或其药学上可接受的盐，溶剂化物、酯、酸、代谢物或前药，其中R1、R2、R3、R4、R5、R6如说明书所定义。本发明还公开了包括式I化合物的药物组合物及本发明化合物在制备用于治疗由BCR-ABL激酶活化介导的病症的药物中的用途。
• Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-<i>N</i>-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chromosome (BMX) Kinase Inhibitor
  作者：Xiaofei Liang、Fengchao Lv、Beilei Wang、Kailin Yu、Hong Wu、Ziping Qi、Zongru Jiang、Cheng Chen、Aoli Wang、Weili Miao、Wenchao Wang、Zhenquan Hu、Juan Liu、Xiaochuan Liu、Zheng Zhao、Li Wang、Shanchuan Zhang、Zi Ye、Chu Wang、Tao Ren、Yinsheng Wang、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.6b01413

  日期：2017.3.9

  BMX is a member of TEC family nonreceptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high selectivity profile (S score(1) = 0.01) against the 468 kinases/mutants in the KINOMEscan evaluation and achieved at least 40-fold selectivity over BTK kinase. Given the fact that BMX mediated signaling pathway is still not fully understood, compound 41 would serve as a useful pharmacological tool to elucidate the detailed mechanism of BMX mediated signaling pathways.