(2S,4S,5S,7S)-5-amino-N-((R)-1-(4-bromophenyl)ethyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide hydrochloride

• 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: (2S,4S,5S,7S)-5-amino-N-((R)-1-(4-bromophenyl)ethyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide hydrochloride
• 英文别名: (2S,4S,5S,7S)-5-amino-N-[(1R)-1-(4-bromophenyl)ethyl]-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-2-propan-2-ylnonanamide;hydrochloride
• 化学式: C₃₃H₅₁BrN₂O₅*ClH
• 分子量: 672.143
• InChiKey: ALNQDDZMEMGJHV-KLCBFBTRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.73
• 重原子数：
  42
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  103
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  tert-butyl (3S,5S,6S,8S)-8-((R)-1-(4-bromophenyl)ethylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以97%的产率得到(2S,4S,5S,7S)-5-amino-N-((R)-1-(4-bromophenyl)ethyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide hydrochloride
  参考文献：
  名称：

  Discovery of highly potent renin inhibitors potentially interacting with the S3′ subsite of renin

  摘要：

  To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC50 < 3 nM) were identified, among which compounds 38 (IC50 = 0.9 nM) and 39 (IC50 = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 mu mol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.08.060

文献信息

• Discovery of highly potent renin inhibitors potentially interacting with the S3′ subsite of renin
  作者：Xiaowei Sun、Xiaoan Wen、Yan-yan Chen、Chen Shi、Chengzhe Gao、Yong Wu、Li-jun Wang、Xiu-hong Yang、Hongbin Sun

  DOI：10.1016/j.ejmech.2015.08.060

  日期：2015.10

  To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC50 < 3 nM) were identified, among which compounds 38 (IC50 = 0.9 nM) and 39 (IC50 = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 mu mol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design. (C) 2015 Elsevier Masson SAS. All rights reserved.