N-(5-(6-chloro-5-(phenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)propionamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(5-(6-chloro-5-(phenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)propionamide
• 英文别名: N-[5-[5-(benzenesulfonamido)-6-chloropyridin-3-yl]-4-methyl-1,3-thiazol-2-yl]propanamide
• 化学式: C₁₈H₁₇ClN₄O₃S₂
• 分子量: 436.943
• InChiKey: YEOFKDOQMIILQR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氯-3-氨基-5-溴吡啶 在 吡啶 、 盐酸 、 三叔丁基膦 、 palladium diacetate 、 caesium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.0h， 生成 N-(5-(6-chloro-5-(phenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)propionamide
  参考文献：
  名称：

  Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor

  摘要：

  PI3K delta, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3K delta inhibitors. Among them compound 151 (CHMFL-PI3K delta-317) displays an IC50 of 6 nM against PI3K delta in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3K delta mediated phosphorylation of Akt T308 but not PI3K delta, beta, gamma mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 mu M. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3K delta armory. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.07.036