methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(5S)-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)]-3-chlorophenyl}propanoate | 905281-21-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(5S)-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)]-3-chlorophenyl}propanoate
• 英文别名: methyl (2S)-3-[4-[(5S)-2-tert-butyl-1,1,3-trioxo-1,2-thiazolidin-5-yl]-3-chlorophenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate
• CAS: 905281-21-2
• 化学式: C₂₂H₃₁ClN₂O₇S
• 分子量: 503.016
• InChiKey: IIDVYMJIWRJKBJ-IRXDYDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  128
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(5S)-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)]-3-chlorophenyl}propanoate 在 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.08h， 生成 (2S)-2-(tert-butoxycarbonyl)amino-3-{3-chloro-4-[(5S)-1,1-dioxido-3-oxoisothiazolidin-5-yl]phenyl}propanoic acid
  参考文献：
  名称：

  Potent Benzimidazole Sulfonamide Protein Tyrosine Phosphatase 1B Inhibitors Containing the Heterocyclic (S)-Isothiazolidinone Phosphotyrosine Mimetic

  摘要：

  Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine ( pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 angstrom resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.

  DOI：

  10.1021/jm0600904
• 作为产物：
  描述：

  (2S)-3-(4-氨基苯基)-2-[(叔丁氧基羰基)氨基]丙酸甲酯 在 盐酸 、 N-氯代丁二酰亚胺 、 锂硼氢 、 四丁基氯化铵 、 palladium diacetate 、 三乙胺 、 sodium nitrite 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.67h， 生成 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(5S)-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)]-3-chlorophenyl}propanoate
  参考文献：
  名称：

  Potent Benzimidazole Sulfonamide Protein Tyrosine Phosphatase 1B Inhibitors Containing the Heterocyclic (S)-Isothiazolidinone Phosphotyrosine Mimetic

  摘要：

  Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine ( pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 angstrom resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.

  DOI：

  10.1021/jm0600904

文献信息

• Potent Benzimidazole Sulfonamide Protein Tyrosine Phosphatase 1B Inhibitors Containing the Heterocyclic (<i>S</i>)-Isothiazolidinone Phosphotyrosine Mimetic
  作者：Andrew P. Combs、Wenyu Zhu、Matthew L. Crawley、Brian Glass、Padmaja Polam、Richard B. Sparks、Dilip Modi、Amy Takvorian、Erin McLaughlin、Eddy W. Yue、Zelda Wasserman、Michael Bower、Min Wei、Mark Rupar、Paul J. Ala、Brian M. Reid、Dawn Ellis、Lucie Gonneville、Thomas Emm、Nancy Taylor、Swamy Yeleswaram、Yanlong Li、Richard Wynn、Timothy C. Burn、Gregory Hollis、Phillip C. C. Liu、Brian Metcalf

  DOI：10.1021/jm0600904

  日期：2006.6.1

  Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine ( pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 angstrom resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.