N-[3-(7-chloro-1-cyclopropyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-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-[3-(7-chloro-1-cyclopropyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide
• 化学式: C₂₄H₁₉ClF₃N₅O₂
• 分子量: 501.895
• InChiKey: SWWMWHGUZWAGKU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  78.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-氨基-6-甲基吡啶 、 N-[3-(7-chloro-1-cyclopropyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide 在 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 仲丁醇 为溶剂， 反应 2.0h， 以123.5 mg的产率得到N-[3-[1-cyclopropyl-7-[(6-methylpyridin-3-yl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

  摘要：

  GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound lli is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.

  DOI：

  10.1021/acs.jmedchem.8b00882
• 作为产物：
  描述：

  2,4-二氯-5-(氯甲基)嘧啶 在 potassium carbonate 、 三乙胺 、 sodium iodide 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 17.0h， 生成 N-[3-(7-chloro-1-cyclopropyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

  摘要：

  GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound lli is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.

  DOI：

  10.1021/acs.jmedchem.8b00882

文献信息

• [EN] EX VIVO PRODUCTION OF PLATELETS FROM HEMATOPOIETIC STEM CELLS AND THE PRODUCT THEREOF<br/>[FR] PRODUCTION DE PLAQUETTES EX VIVO À PARTIR DE CELLULES SOUCHES HÉMATOPOÏÉTIQUES ET LEUR PRODUIT
  申请人：IRM LLC

  公开号：WO2014138485A1

  公开（公告）日：2014-09-12

  The present invention relates to a method of producing platelets (characterized by CD41+ and CD42+) from hematopoietic stem cells ex vivo. The invention further relates to a composition comprising the ex vivo produced platelets and a reagent comprising an aryl hydrocarbon antagonist and its use in autologous or allogeneic transfusion for the treatment of thrombocytopenia, thereby treating disease and conditions that caused the thrombocytopenia.
• First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia
  作者：Hanna Cho、Injae Shin、Eunhye Ju、Seunghye Choi、Wooyoung Hur、Haelee Kim、Eunmi Hong、Nam Doo Kim、Hwan Geun Choi、Nathanael S. Gray、Taebo Sim

  DOI：10.1021/acs.jmedchem.8b00882

  日期：2018.9.27

  GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound lli is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.