(R)-2-{4-chloro-N-{[(1s,3s)-3-cyanocyclobutyl]methyl}-phenylsulfonamido}-5,5,5-trifluoropentanamide | 1370705-45-5

• 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-{[(1s,3s)-3-cyanocyclobutyl]methyl}-phenylsulfonamido}-5,5,5-trifluoropentanamide
• CAS: 1370705-45-5
• 化学式: C₁₇H₁₉ClF₃N₃O₃S
• 分子量: 437.87
• InChiKey: DMINKKLAOYLYLD-TYNCELHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.08
• 重原子数：
  28.0
• 可旋转键数：
  8.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  104.26
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (R)-2-{4-chloro-N-{[(1s,3s)-3-cyanocyclobutyl]methyl}-phenylsulfonamido}-5,5,5-trifluoropentanamide 在 盐酸羟胺 、 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 48.0h， 生成
  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：

  3-(羟甲基)环丁烷-1-腈 、 (2R)-2-[[(4-氯苯基)磺酰基]氨基]-5,5,5-三氟-戊酰胺 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-{[(1s,3s)-3-cyanocyclobutyl]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

文献信息

• 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
  作者：Antonia F. Stepan、Chakrapani Subramanyam、Ivan V. Efremov、Jason K. Dutra、Theresa J. O’Sullivan、Kenneth J. DiRico、W. Scott McDonald、Annie Won、Peter H. Dorff、Charles E. Nolan、Stacey L. Becker、Leslie R. Pustilnik、David R. Riddell、Gregory W. Kauffman、Bethany L. Kormos、Liming Zhang、Yasong Lu、Steven H. Capetta、Michael E. Green、Kapil Karki、Evelyn Sibley、Kevin P. Atchison、Andrew J. Hallgren、Christine E. Oborski、Ashley E. Robshaw、Blossom Sneed、Christopher J. O’Donnell

  DOI：10.1021/jm300094u

  日期：2012.4.12

  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.