tert-butyl N-[N'-[[3,5-dichloro-4-[(2-methylsulfanylacetyl)amino]phenyl]methyl]-N-[3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carbonyl]carbamimidoyl]carbamate | 1402164-86-6

• 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: tert-butyl N-[N'-[[3,5-dichloro-4-[(2-methylsulfanylacetyl)amino]phenyl]methyl]-N-[3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carbonyl]carbamimidoyl]carbamate
• CAS: 1402164-86-6
• 化学式: C₂₈H₃₁Cl₂N₅O₆S
• 分子量: 636.556
• InChiKey: HQLSFGCDKPDDHA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  169
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[N'-[[3,5-dichloro-4-[(2-methylsulfanylacetyl)amino]phenyl]methyl]-N-[3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carbonyl]carbamimidoyl]carbamate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以15 mg的产率得到N-amino-(3,5-dichloro-4-(2-(methylthio)acetamidobenzylamino)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
• 作为产物：
  描述：

  2-甲基-2-丙基[(甲硫基)亚氨代甲酰基]氨基甲酸酯 在 正丙胺 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 21.0h， 生成 tert-butyl N-[N'-[[3,5-dichloro-4-[(2-methylsulfanylacetyl)amino]phenyl]methyl]-N-[3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carbonyl]carbamimidoyl]carbamate
  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