N-[N'-[[3-chloro-5-[(E)-4-hydroxybut-1-enyl]phenyl]methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide | 917386-29-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-[N'-[[3-chloro-5-[(E)-4-hydroxybut-1-enyl]phenyl]methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide
• CAS: 917386-29-9
• 化学式: C₂₄H₂₅ClN₄O₄
• 分子量: 468.94
• InChiKey: FHMCMYUUOIHQHV-HWKANZROSA-N

物化性质

• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-[N'-[(3-bromo-5-chlorophenyl)methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide 、 (E)-trimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane 在 potassium phosphate 、 四(三苯基膦)钯 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以8%的产率得到N-[N'-[[3-chloro-5-[(E)-4-hydroxybut-1-enyl]phenyl]methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-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