N-(4-methyl-3-(1-methyl-7-(3-morpholinopropylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide

• 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: N-(4-methyl-3-(1-methyl-7-(3-morpholinopropylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide
• 英文别名: N-(4-methyl-3-(1-methyl-7-((3-morpholinopropyl)amino)-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(trifluoromethyl)benzamide；N-[4-methyl-3-[1-methyl-7-(3-morpholin-4-ylpropylamino)-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide
• 化学式: C₂₉H₃₂F₃N₇O₃
• 分子量: 583.613
• InChiKey: FWVLVEFKMVXALX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  42
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  N-(4-methyl-3-(((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methyl)amino)phenyl)-3-(trifluoromethyl)benzamide 在 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 49.0h， 生成 N-(4-methyl-3-(1-methyl-7-(3-morpholinopropylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

  摘要：

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

  DOI：

  10.1021/acs.jmedchem.5b01618

文献信息

• Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway
  作者：Namkyoung Kim、Injae Shin、Younghoon Kim、Eunhye Jeon、Jiwon Lee、Chaeyoung Lee、Yunju Nam、Sumin Lee、Eunhye Ju、Chan Kim、Woolim Son、SeongShick Ryu、Minjoo Ko、Taebo Sim

  DOI：10.3389/fonc.2021.768022

  日期：——

  We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest

  RAS 突变体涉及大约 30% 的人类癌症，由于相对光滑的蛋白质表面和模糊的结合口袋，RAS 突变体被认为是不可成药的靶点。在我们之前的研究中，我们已经证明 GNF-7 是一种多靶向激酶抑制剂，对 NRAS-G12D 转化的 Ba/F3 细胞具有有效的抗增殖活性。基于我们使用 mtRAS 转化的 Ba/F3 细胞的进一步分析，我们发现了一系列嘧啶[4,5-d]pyrimidin-2-one 类似物作为 mtRAS 信号通路阻滞剂。此外，我们的努力扩大了对 mtRAS 癌细胞的评估，这表明这些物质还能够强烈抑制各种携带 KRAS-G12D (AsPC-1)、KRAS-G12V (SW480、DU-145) 的癌细胞的增殖)、KRAS-G12C (H358)、KRAS-G13D (MDA-MB-231)、KRAS-Q61L (HT-29) 和 NRAS-Q61L (OCI-AML3)。我们在此报告了新型且有效的
• Discovery of 2-((3-Amino-4-methylphenyl)amino)-<i>N</i>-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia
  作者：Xiaofei Liang、Xiaochuan Liu、Beilei Wang、Fengming Zou、Aoli Wang、Shuang Qi、Cheng Chen、Zheng Zhao、Wenchao Wang、Ziping Qi、Fengchao Lv、Zhenquan Hu、Li Wang、Shanchun Zhang、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.5b01618

  日期：2016.3.10

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.