(R)-2-{4-chloro-N-[(1-cyanocyclopropyl)methyl]-phenylsulfonamido}-5,5,5-trifluoropentanamide | 1370705-47-7

• 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: (R)-2-{4-chloro-N-[(1-cyanocyclopropyl)methyl]-phenylsulfonamido}-5,5,5-trifluoropentanamide
• 英文别名: (2R)-2-[(4-chlorophenyl)sulfonyl-[(1-cyanocyclopropyl)methyl]amino]-5,5,5-trifluoropentanamide
• CAS: 1370705-47-7
• 化学式: C₁₆H₁₇ClF₃N₃O₃S
• 分子量: 423.843
• InChiKey: ZLFSNVWAHBDKKJ-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (R)-2-{4-chloro-N-[(1-cyanocyclopropyl)methyl]-phenylsulfonamido}-5,5,5-trifluoropentanamide 在 三氟化硼乙醚 、 羟胺 作用下， 以 乙醇 、 水 、 1,2-二氯乙烷 为溶剂， 生成 (R)-2-{N-{[1-(1,2,4-oxadiazol-3-yl)cyclopropyl]methyl}-4-chlorophenylsulfonamido}-5,5,5-trifluoropentanamide
  参考文献：
  名称：

  Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active γ-Secretase Inhibitor

  摘要：

  Replacement of the central, para-substituted fluorophenyl ring in the gamma-secretase inhibitor 1 (BMS-708,163) with the bic-yclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (similar to 4-fold up arrow C-max and AUC values relative to 1) in a mouse model of gamma-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., gamma-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.

  DOI：

  10.1021/jm300094u
• 作为产物：
  描述：

  (2R)-2-[[(4-氯苯基)磺酰基]氨基]-5,5,5-三氟-戊酰胺 、 1-(羟基甲基)环丙烷甲腈 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 以52%的产率得到(R)-2-{4-chloro-N-[(1-cyanocyclopropyl)methyl]-phenylsulfonamido}-5,5,5-trifluoropentanamide
  参考文献：
  名称：

  Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active γ-Secretase Inhibitor

  摘要：

  Replacement of the central, para-substituted fluorophenyl ring in the gamma-secretase inhibitor 1 (BMS-708,163) with the bic-yclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (similar to 4-fold up arrow C-max and AUC values relative to 1) in a mouse model of gamma-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., gamma-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.

  DOI：

  10.1021/jm300094u