1-(2-chloro-7-isopropylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 1-(2-chloro-7-isopropylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea
• 英文别名: 1-(2-Chloro-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-6-yl)-3-[2-(trifluoromethyl)pyridin-4-yl]urea；1-(2-chloro-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-6-yl)-3-[2-(trifluoromethyl)pyridin-4-yl]urea
• 化学式: C₁₆H₁₄ClF₃N₆O
• 分子量: 398.775
• InChiKey: VBFBTODZEVJUIC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  84.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate 在 二苯基膦叠氮化物 、 水 、 三乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 5.5h， 生成 1-(2-chloro-7-isopropylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea
  参考文献：
  名称：

  Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood

  摘要：

  The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases, and there is a need for suitable compounds to explore the therapeutic potential of this target. Here, we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. High doses of the initial lead compound led to tumor stasis in an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but this compound suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In the second optimization step, masking one of the hydrogen-bond donors of the central urea moiety through an intramolecular interaction led to improved potency in whole blood. This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.

  DOI：

  10.1021/acs.jmedchem.0c01246