[5-(甲基氨基甲酰基)吡啶-3-基]硼酸 | 1246022-34-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: [5-(甲基氨基甲酰基)吡啶-3-基]硼酸
• 英文名称: (5-(methylcarbamoyl)pyridin-3-yl)boronic acid
• 英文别名: 5-(methylaminoformyl)pyridin-3-ylboronic acid；[5-(methylcarbamoyl)pyridin-3-yl]boronic acid
• CAS: 1246022-34-3
• 化学式: C₇H₉BN₂O₃
• 分子量: 179.971
• InChiKey: RCPVUDMPXOZRCM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.88
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  82.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [5-(甲基氨基甲酰基)吡啶-3-基]硼酸 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 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 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 34.0h， 生成
  参考文献：
  名称：

  Discovery of (E)-N¹-(3-Fluorophenyl)-N³-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

  摘要：

  Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.

  DOI：

  10.1021/acs.jmedchem.9b00176

文献信息

• Synthesis, Structure–Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity
  作者：Jessica N. Akester、Paul Njaria、Aloysius Nchinda、Claire Le Manach、Alissa Myrick、Vinayak Singh、Nina Lawrence、Mathew Njoroge、Dale Taylor、Atica Moosa、Anthony J. Smith、Elizabeth J. Brooks、Anne J. Lenaerts、Gregory T. Robertson、Thomas R. Ioerger、Rudolf Mueller、Kelly Chibale

  DOI：10.1021/acsinfecdis.0c00252

  日期：2020.7.10

  2-aminoquinazolinone hit compound, sulfone 1 which was optimized for solubility by replacing the sulfone moiety with a sulfoxide 2. The synthesis and structure–activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound 2 displayed favorable in vitro properties and was therefore selected for in vivo

  表型全细胞筛选针对补充有吐温80和铁（GASTE-Fe）的甘油-丙氨酸-盐中的结核分枝杆菌（Mtb）导致鉴定出2-氨基喹唑啉酮命中化合物砜1，该化合物可通过替换来优化溶解度带有亚砜的砜部分2。合成和结构-活性关系（SAR）研究确定了几种具有有效抗分枝杆菌活性的化合物，它们在代谢上稳定且无细胞毒性。化合物2表现出良好的体外特性，因此被选择用于体内药代动力学（PK）研究，发现它被广泛代谢为砜1。两种衍生物均显示出有希望的PK参数。但是，当评估2在急性TB感染小鼠模型中的体内功效时，发现它没有活性。为了了解体外和体内差异，随后使用在不同培养基中培养的不同Mtb菌株在体外对化合物2进行了重新测试。这表明仅在含甘油的介质中观察到了活性，并导致了以下假设：甘油不被Mtb用作主要碳源。如先前所观察到的，在小鼠肺中的这种作用。自发抗性突变体的产生和全基因组测序研究提供了对这一假说的支持，该研究揭示了映射到
• Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium
  作者：Xiaofei Liang、Zongru Jiang、Zhenghui Huang、Feng Li、Cheng Chen、Chen Hu、Wenliang Wang、Zhenquan Hu、Qingwang Liu、Beilei Wang、Li Wang、Ziping Qi、Jing Liu、Lubin Jiang、Qingsong Liu

  DOI：10.1016/j.ejmech.2019.112012

  日期：2020.2

  Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria. (C) 2019 Elsevier Masson SAS. All rights reserved.
• Discovery of (<i>E</i>)-<i>N</i>¹-(3-Fluorophenyl)-<i>N</i>³-(3-(2-(pyridin-2-yl)vinyl)-1<i>H</i>-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
  作者：Xuesong Liu、Beilei Wang、Cheng Chen、Ziping Qi、Fengming Zou、Junjie Wang、Chen Hu、Aoli Wang、Juan Ge、Qingwang Liu、Kailin Yu、Zhenquan Hu、Zongru Jiang、Wei Wang、Li Wang、Wenchao Wang、Tao Ren、Mingfeng Bai、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.9b00176

  日期：2019.5.23

  Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.