(2-氨基-4-氨基甲酰基苯基)硼酸 | 1040400-88-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (2-氨基-4-氨基甲酰基苯基)硼酸
• 英文名称: (2-Amino-4-carbamoylphenyl)boronic acid
• CAS: 1040400-88-1
• 化学式: C₇H₉BN₂O₃
• 分子量: 179.971
• InChiKey: OXDIYMNQYJTIQC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.95
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  110
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-chloro-3-iodo-6,7-dimethoxyquinoline 、 (2-氨基-4-氨基甲酰基苯基)硼酸 在 四(三苯基膦)钯 、 caesium carbonate 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 反应 16.0h， 生成 2,3-dimethoxy-11H-indolo[3,2-c]quinoline-9-carboxamide
  参考文献：
  名称：

  Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4

  摘要：

  IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPSand R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and clogP. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNF alpha in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.056

文献信息

• Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4
  作者：L. Nathan Tumey、Diane H. Boschelli、Niala Bhagirath、Jaechul Shim、Elizabeth A. Murphy、Deborah Goodwin、Eric M. Bennett、Mengmeng Wang、Lih-Ling Lin、Barry Press、Marina Shen、Richard K. Frisbie、Paul Morgan、Shashi Mohan、Julia Shin、Vikram R. Rao

  DOI：10.1016/j.bmcl.2014.03.056

  日期：2014.5

  IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPSand R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and clogP. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNF alpha in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice. (C) 2014 Elsevier Ltd. All rights reserved.