tert-butyl (1S)-1-(3-cyano-4-hydroxybenzyl)-2-oxo-2-(pentylamino)ethylcarbamate | 221077-49-2

• 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: tert-butyl (1S)-1-(3-cyano-4-hydroxybenzyl)-2-oxo-2-(pentylamino)ethylcarbamate
• 英文别名: tert-butyl N-[(2S)-3-(3-cyano-4-hydroxyphenyl)-1-oxo-1-(pentylamino)propan-2-yl]carbamate
• CAS: 221077-49-2
• 化学式: C₂₀H₂₉N₃O₄
• 分子量: 375.468
• InChiKey: RFAGCGLAYPFPII-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (1S)-1-(3-cyano-4-hydroxybenzyl)-2-oxo-2-(pentylamino)ethylcarbamate 在 potassium carbonate 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 4.0h， 生成 methyl 2-{4-[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-oxo-3-(pentylamino)propyl]-2-cyanophenoxy}acetate
  参考文献：
  名称：

  Investigation of Potential Bioisosteric Replacements for the Carboxyl Groups of Peptidomimetic Inhibitors of Protein Tyrosine Phosphatase 1B:  Identification of a Tetrazole-Containing Inhibitor with Cellular Activity

  摘要：

  Protein tyrosine phosphatases (PTPs) constitute a diverse family of enzymes that, together with protein tyrosine kinases, control the level of intracellular tyrosine phosphorylation, thus regulating many cellular functions. PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. We previously reported a series of small molecular weight peptidomimetics as competitive inhibitors of PTP1B, with the most active analogues having K-i values in the low nanomolar range. Furthermore, we confirmed that the O-carboxymethyl salicylic acid moiety is a remarkably effective novel phosphotyrosine mimetic. Because of the low cell permeability of this compound class, it was important to investigate the possibility of replacing one or both of the remaining carboxyl groups while maintaining PTP1B inhibitory activity. The analogues described herein further support the importance of an acidic functionality at both positions of the tyrosine head moiety. An important discovery was the ortho tetrazole analogue 29 (K-i = 2.0 muM), which was equipotent to the dicarboxylic acid analogue 2 (K-i = 2.0 muM). Solution of the X-ray cocrystal structure of the ortho tetrazole analogue 29 bound to PTP1B revealed that the tetrazole moiety is well-accommodated in the active site and binds in a fashion similar to the ortho carboxylate analogue 2 reported previously. This novel monocarboxylic acid analogue revealed significantly higher Caco-2 cell permeability as compared to all previous compounds. Furthermore, compound 29 exhibited modest enhancement of insulin-stimulated 2-deoxyglucose uptake by L6 myocytes.

  DOI：

  10.1021/jm011100y
• 作为产物：
  描述：

  tert-butyl (1S)-1-(4-hydroxy-3-iodobenzyl)-2-oxo-2-(pentylamino)ethylcarbamate 在 四(三苯基膦)钯 zinc(II) cyanide 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 16.0h， 以38%的产率得到tert-butyl (1S)-1-(3-cyano-4-hydroxybenzyl)-2-oxo-2-(pentylamino)ethylcarbamate
  参考文献：
  名称：

  Inhibitors of protein tyrosine phosphatase

  摘要：

  本发明涉及小分子量、非肽类的蛋白酪氨酸磷酸酶1（PTP1）的化学式I和II的抑制剂，用于治疗和/或预防非胰岛素依赖型糖尿病（NIDDM）。

  公开号：

  US06353023B1

文献信息

• Inhibitors of protein tyrosine phosphatase
  申请人：Pharmacia & Upjohn Company

  公开号：US06353023B1

  公开（公告）日：2002-03-05

  The present invention comprises small molecular weight, non-peptidic inhibitors of formula I and II of Protein Tyrosine Phosphatase 1 (PTP1) which are useful for the treatment and/or prevention of Non-Insulin Dependent Diabetes Mellitus (NIDDM).

  本发明涉及小分子量、非肽类的蛋白酪氨酸磷酸酶1（PTP1）的化学式I和II的抑制剂，用于治疗和/或预防非胰岛素依赖型糖尿病（NIDDM）。
• Investigation of Potential Bioisosteric Replacements for the Carboxyl Groups of Peptidomimetic Inhibitors of Protein Tyrosine Phosphatase 1B:  Identification of a Tetrazole-Containing Inhibitor with Cellular Activity
  作者：Charlotta Liljebris、Scott D. Larsen、Derek Ogg、Barbara J. Palazuk、John E. Bleasdale

  DOI：10.1021/jm011100y

  日期：2002.4.1

  Protein tyrosine phosphatases (PTPs) constitute a diverse family of enzymes that, together with protein tyrosine kinases, control the level of intracellular tyrosine phosphorylation, thus regulating many cellular functions. PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. We previously reported a series of small molecular weight peptidomimetics as competitive inhibitors of PTP1B, with the most active analogues having K-i values in the low nanomolar range. Furthermore, we confirmed that the O-carboxymethyl salicylic acid moiety is a remarkably effective novel phosphotyrosine mimetic. Because of the low cell permeability of this compound class, it was important to investigate the possibility of replacing one or both of the remaining carboxyl groups while maintaining PTP1B inhibitory activity. The analogues described herein further support the importance of an acidic functionality at both positions of the tyrosine head moiety. An important discovery was the ortho tetrazole analogue 29 (K-i = 2.0 muM), which was equipotent to the dicarboxylic acid analogue 2 (K-i = 2.0 muM). Solution of the X-ray cocrystal structure of the ortho tetrazole analogue 29 bound to PTP1B revealed that the tetrazole moiety is well-accommodated in the active site and binds in a fashion similar to the ortho carboxylate analogue 2 reported previously. This novel monocarboxylic acid analogue revealed significantly higher Caco-2 cell permeability as compared to all previous compounds. Furthermore, compound 29 exhibited modest enhancement of insulin-stimulated 2-deoxyglucose uptake by L6 myocytes.