N-(amino((3,5-dimethylbenzyl)amino)methylene)-3-(4-methoxyphenyl)-5-methylisothiazole-4-carboxamide | 917385-98-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(amino((3,5-dimethylbenzyl)amino)methylene)-3-(4-methoxyphenyl)-5-methylisothiazole-4-carboxamide
• CAS: 917385-98-9
• 化学式: C₂₂H₂₄N₄O₂S
• 分子量: 408.524
• InChiKey: ADJMTUATPOHZTB-UHFFFAOYSA-N

物化性质

• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.99
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  89.6
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  5-(4-methoxyphenyl)-1,3-dimethyl-1H-pyrazole-4-carboxylic acid 、 3-(3,4-dimethoxyphenyl)-5-methylisoxazole-4-carboxylic acid 在 N,N-二异丙基乙胺 、 ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 24.0h， 生成 N-(amino((3,5-dimethylbenzyl)amino)methylene)-3-(4-methoxyphenyl)-5-methylisothiazole-4-carboxamide
  参考文献：
  名称：

  Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

  摘要：

  This report describes the discovery and optimizition of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A beta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A beta levels were not obtained.

  DOI：

  10.1021/jm300931y