N-Boc-Chg-Pro-OMe | 190509-47-8

• 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: N-Boc-Chg-Pro-OMe
• 英文别名: methyl (2S)-1-[(2R)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]pyrrolidine-2-carboxylate
• CAS: 190509-47-8
• 化学式: C₁₉H₃₂N₂O₅
• 分子量: 368.473
• InChiKey: SAOCKOWHTXPPIA-LSDHHAIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.62
• 重原子数：
  26.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  84.94
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-Boc-Chg-Pro-OMe 在 N-甲基吗啉 、 lithium hydroxide 、 氯化铵 、 1-羟基苯并三唑 、 caesium carbonate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 生成 {(R)-2-[(S)-2-(2-Carbamoylmethoxy-5-chloro-benzylcarbamoyl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position

  摘要：

  As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

  DOI：

  10.1021/jm9801713
• 作为产物：
  描述：

  L-脯氨酸甲酯盐酸盐 、 Boc-D-环己基甘氨酸 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 N-Boc-Chg-Pro-OMe
  参考文献：
  名称：

  Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position

  摘要：

  As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

  DOI：

  10.1021/jm9801713

文献信息

• Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases
  作者：Sarah E. Poplawski、Jack H. Lai、David G. Sanford、James L. Sudmeier, Wengen Wu、William W. Bachovchin

  DOI：10.1021/jm100972f

  日期：2011.4.14

  Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency > 100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to I. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.