L-alanine but-2-yl ester hydrochloride | 926308-54-5

• 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: L-alanine but-2-yl ester hydrochloride
• 英文别名: L-alanine tert-butyl ester hydrochloride；butan-2-yl (2S)-2-aminopropanoate;hydrochloride
• CAS: 926308-54-5
• 化学式: C₇H₁₅NO₂*ClH
• 分子量: 181.663
• InChiKey: QZMNFWVOLSBPBY-PQAGPIFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  11
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  52.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  L-alanine but-2-yl ester hydrochloride 、 (2R,3R,4R,5R)-2-(2-amino-6-methoxypurin-9-yl)-5-(dichlorophosphoryloxymethyl)-3-methyloxolane-3,4-diol 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 以90 mg的产率得到(2S,2'S)-di-sec-butyl 2,2'-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate
  参考文献：
  名称：

  Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

  摘要：

  We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both D and L., and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 mu M, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.

  DOI：

  10.1021/jm2011673

文献信息

• Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents
  作者：Christopher McGuigan、Karolina Madela、Mohamed Aljarah、Claire Bourdin、Maria Arrica、Emma Barrett、Sarah Jones、Alexander Kolykhalov、Blair Bleiman、K. Dawn Bryant、Babita Ganguly、Elena Gorovits、Geoffrey Henson、Damound Hunley、Jeff Hutchins、Jerry Muhammad、Aleksandr Obikhod、Joseph Patti、C. Robin Walters、Jin Wang、John Vernachio、Changalvala V. S. Ramamurty、Srinivas K. Battina、Stanley Chamberlain

  DOI：10.1021/jm2011673

  日期：2011.12.22

  We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both D and L., and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 mu M, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.