(1S)-<1-(cyclohexylmethyl)-2-(diethoxyphosphinyl)-2-hydroxyethyl>carbamic acid, 1,1-dimethylethyl ester

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: (1S)-<1-(cyclohexylmethyl)-2-(diethoxyphosphinyl)-2-hydroxyethyl>carbamic acid, 1,1-dimethylethyl ester
• 英文别名: tert-butyl N-[(2S)-3-cyclohexyl-1-diethoxyphosphoryl-1-hydroxypropan-2-yl]carbamate
• 化学式: C₁₈H₃₆NO₆P
• 分子量: 393.461
• InChiKey: VEVGAIVYASGYHB-VYRBHSGPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  94.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1S)-<1-(cyclohexylmethyl)-2-(diethoxyphosphinyl)-2-hydroxyethyl>carbamic acid, 1,1-dimethylethyl ester 在 盐酸 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 乙酸乙酯 为溶剂， 反应 2.33h， 生成 (1S,2S)-N-<1-(cyclohexylmethyl)-2-(diethoxyphosphinyl)-2-hydroxyethyl>-N²--L-phenylalanyl>-L-leucinamide
  参考文献：
  名称：

  .alpha.-Hydroxy Phosphinyl-Based Inhibitors of Human Renin

  摘要：

  The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P-2 possessed better in vitro activity than the corresponding P-2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P-3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mu mol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.

  DOI：

  10.1021/jm00022a022
• 作为产物：
  描述：

  2-甲基-2-丙基[(2S)-1-环己基-3-氧代-2-丙基]氨基甲酸酯 、 亚磷酸二乙酯 在 potassium fluoride 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以77.4%的产率得到(1S)-<1-(cyclohexylmethyl)-2-(diethoxyphosphinyl)-2-hydroxyethyl>carbamic acid, 1,1-dimethylethyl ester
  参考文献：
  名称：

  .alpha.-Hydroxy Phosphinyl-Based Inhibitors of Human Renin

  摘要：

  The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P-2 possessed better in vitro activity than the corresponding P-2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P-3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mu mol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.

  DOI：

  10.1021/jm00022a022

文献信息

• .alpha.-Hydroxy Phosphinyl-Based Inhibitors of Human Renin
  作者：Dinesh V. Patel、Katherine Rielly-Gauvin、Denis E. Ryono、Charles A. Free、W. Lynn Rogers、Sandra A. Smith、Jack M. DeForrest、Robert S. Oehl、Edward W. Petrillo

  DOI：10.1021/jm00022a022

  日期：1995.10

  The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P-2 possessed better in vitro activity than the corresponding P-2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P-3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mu mol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.