(3S)-4-(1,3-dihydroisoindol-2-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoic acid | 847928-33-0

• 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: (3S)-4-(1,3-dihydroisoindol-2-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoic acid
• CAS: 847928-33-0
• 化学式: C₁₇H₂₂N₂O₅
• 分子量: 334.372
• InChiKey: GRKVUMYAINQAOC-ZDUSSCGKSA-N

物化性质

• 沸点：
  563.8±50.0 °C(Predicted)
• 密度：
  1.267±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S)-4-(1,3-dihydroisoindol-2-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoic acid 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 (S)-2-amino-4-(5-(bis(4-fluorophenyl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-(isoindolin-2-yl)butane-1,4-dione dihydrochloride
  参考文献：
  名称：

  Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?

  摘要：

  This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.

  DOI：

  10.1021/jm200383j
• 作为产物：
  描述：

  Boc-L-天冬氨酸 4-苄酯 在 palladium on activated charcoal N-羟基丁二酰亚胺 、 氢气 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 生成 (3S)-4-(1,3-dihydroisoindol-2-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoic acid
  参考文献：
  名称：

  Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8

  摘要：

  DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type 11 diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC50 value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S I site of DPP8 may be larger than that of DPPIV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.11.023

文献信息

• Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?
  作者：Sebastiaan Van Goethem、Veerle Matheeussen、Jurgen Joossens、Anne-Marie Lambeir、Xin Chen、Ingrid De Meester、Achiel Haemers、Koen Augustyns、Pieter Van der Veken

  DOI：10.1021/jm200383j

  日期：2011.8.25

  This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.
• Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8
  作者：Weir-Torn Jiaang、Yuan-Shou Chen、Tsu Hsu、Ssu-Hui Wu、Chia-Hui Chien、Chung-Nien Chang、Sheng-Ping Chang、Shiow-Ju Lee、Xin Chen

  DOI：10.1016/j.bmcl.2004.11.023

  日期：2005.2

  DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type 11 diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC50 value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S I site of DPP8 may be larger than that of DPPIV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline. (C) 2004 Elsevier Ltd. All rights reserved.