6-chloro-N-(cyclopropylmethyl)-3-(1H-indazol-6-yl)imidazo[1,2-b]pyridazin-8-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 6-chloro-N-(cyclopropylmethyl)-3-(1H-indazol-6-yl)imidazo[1,2-b]pyridazin-8-amine
• 化学式: C₁₇H₁₅ClN₆
• 分子量: 338.799
• InChiKey: WBZBSNMQILYLLL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  70.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  8-溴-6-氯咪唑并[1,2-B]哒嗪 在 N-溴代丁二酰亚胺(NBS) 、 1,1'-bis(di-tertbutylphosphino)ferrocene 、 palladium diacetate 、 sodium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 氯仿 、 水 为溶剂， 反应 18.0h， 生成 6-chloro-N-(cyclopropylmethyl)-3-(1H-indazol-6-yl)imidazo[1,2-b]pyridazin-8-amine
  参考文献：
  名称：

  Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease

  摘要：

  A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1 alpha (IRE1 alpha), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1 alpha oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IREl1 alpha kinase domain that would be incompatible with back-to-back dimerization of the IRE1 alpha protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1 alpha protein conformations and can guide the discovery of highly selective ligands for the IRE1 alpha kinase site that allosterically inhibit the endoribonuclease.

  DOI：

  10.1021/acs.jmedchem.8b01721

文献信息

• Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease
  作者：Giampiero Colombano、John J. Caldwell、Thomas P. Matthews、Chitra Bhatia、Amar Joshi、Tatiana McHardy、Ngai Yi Mok、Yvette Newbatt、Lisa Pickard、Jade Strover、Somaieh Hedayat、Michael I. Walton、Stephanie M. Myers、Alan M. Jones、Harry Saville、Craig McAndrew、Rosemary Burke、Suzanne A. Eccles、Faith E. Davies、Richard Bayliss、Ian Collins

  DOI：10.1021/acs.jmedchem.8b01721

  日期：2019.3.14

  A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1 alpha (IRE1 alpha), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1 alpha oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IREl1 alpha kinase domain that would be incompatible with back-to-back dimerization of the IRE1 alpha protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1 alpha protein conformations and can guide the discovery of highly selective ligands for the IRE1 alpha kinase site that allosterically inhibit the endoribonuclease.