methyl 3-(1-amino-2-chloroethylideneamino)-5-bromobenzo[b]thiophene-2-carboxylate hydrochloride | 1036380-76-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: methyl 3-(1-amino-2-chloroethylideneamino)-5-bromobenzo[b]thiophene-2-carboxylate hydrochloride
• CAS: 1036380-76-3
• 化学式: C₁₂H₁₀BrClN₂O₂S*ClH
• 分子量: 398.108
• InChiKey: ZWBSTYVGWBPSDN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  20.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  64.68
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  methyl 3-(1-amino-2-chloroethylideneamino)-5-bromobenzo[b]thiophene-2-carboxylate hydrochloride 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 7-bromo-2-(chloromethyl)-thieno[2,3-d]pyrimidin-4(3H)-one
  参考文献：
  名称：

  对蛋白激酶 Pim-1 具有亚纳摩尔亲和力的选择性双底物抑制剂

  摘要：

  有效和选择性： Pim 家族蛋白激酶 (PKs) 的 ATP 结合口袋结构的独特性质被用于开发双底物抑制剂和具有亚纳摩尔亲和力的荧光探针。合成了富含精氨酸的肽与两个 ATP 模拟支架的结合物，并作为 Pim-1 的抑制剂进行了测试。针对一组 124 种蛋白激酶，一种新型 ARC-PIM 偶联物选择性抑制 Pim 家族的 PK。

  DOI：

  10.1002/cmdc.201300042
• 作为产物：
  描述：

  2-氟-5-溴苯腈 在 盐酸 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 methyl 3-(1-amino-2-chloroethylideneamino)-5-bromobenzo[b]thiophene-2-carboxylate hydrochloride
  参考文献：
  名称：

  对蛋白激酶 Pim-1 具有亚纳摩尔亲和力的选择性双底物抑制剂

  摘要：

  有效和选择性： Pim 家族蛋白激酶 (PKs) 的 ATP 结合口袋结构的独特性质被用于开发双底物抑制剂和具有亚纳摩尔亲和力的荧光探针。合成了富含精氨酸的肽与两个 ATP 模拟支架的结合物，并作为 Pim-1 的抑制剂进行了测试。针对一组 124 种蛋白激酶，一种新型 ARC-PIM 偶联物选择性抑制 Pim 家族的 PK。

  DOI：

  10.1002/cmdc.201300042

文献信息

• PIM KINASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS
  申请人：Penning Thomas D.

  公开号：US20080161559A1

  公开（公告）日：2008-07-03

  Inhibitors of Pim kinases, ways to make them and methods of treating patients using them are disclosed.

  抑制Pim激酶的抑制剂，制备方法以及利用它们治疗患者的方法被披露。
• Discovery of 3<i>H</i>-Benzo[4,5]thieno[3,2-<i>d</i>]pyrimidin-4-ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM) Kinases
  作者：Zhi-Fu Tao、Lisa A. Hasvold、Joel D. Leverson、Edward K. Han、Ran Guan、Eric F. Johnson、Vincent S. Stoll、Kent D. Stewart、Geoff Stamper、Nirupama Soni、Jennifer J. Bouska、Yan Luo、Thomas J. Sowin、Nan-Horng Lin、Vincent S. Giranda、Saul H. Rosenberg、Thomas D. Penning

  DOI：10.1021/jm900943h

  日期：2009.11.12

  Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been Found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K-i values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC50 values. For example, compound 14j inhibited the growth of K562 cells with an EC50 value of 1.7 mu M and showed K-i values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein bin-ling, and no CYP inhibition below 20 mu M concentration.