4-chloro-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(thiophen-2-yl)benzamido)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: 4-chloro-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(thiophen-2-yl)benzamido)benzamide
• 英文别名: 4-chloro-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(3-thiophen-2-ylbenzoyl)amino]benzamide
• 化学式: C₃₁H₂₈ClF₃N₄O₂S
• 分子量: 613.103
• InChiKey: UEJBWZOJPCFIOO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  92.9
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-氨基-4-氯苯甲酸甲酯 在 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 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.0h， 生成 4-chloro-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(thiophen-2-yl)benzamido)benzamide
  参考文献：
  名称：

  Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

  摘要：

  Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.03.064

文献信息

• Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors
  作者：Sreekanth A. Ramachandran、Pradeep S. Jadhavar、Sandeep K. Miglani、Manvendra P. Singh、Deepak P. Kalane、Anil K. Agarwal、Balaji D. Sathe、Kakoli Mukherjee、Ashu Gupta、Srijan Haldar、Mohd Raja、Siddhartha Singh、Son M. Pham、Sarvajit Chakravarty、Kevin Quinn、Sebastian Belmar、Ivan E. Alfaro、Christopher Higgs、Sebastian Bernales、Francisco J. Herrera、Roopa Rai

  DOI：10.1016/j.bmcl.2017.03.064

  日期：2017.5

  Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice. (C) 2017 Elsevier Ltd. All rights reserved.