N-(amino(3-chloro-5-(thiophen-3-yl)benzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide | 917386-28-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(amino(3-chloro-5-(thiophen-3-yl)benzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide
• 英文别名: N-[N'-[(3-chloro-5-thiophen-3-ylphenyl)methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide
• CAS: 917386-28-8
• 化学式: C₂₄H₂₁ClN₄O₃S
• 分子量: 480.975
• InChiKey: UTTBFSIUUZDEJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-噻吩硼酸 、 N-[N'-[(3-bromo-5-chlorophenyl)methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide 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30%的产率得到N-(amino(3-chloro-5-(thiophen-3-yl)benzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-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