N-<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>-4,5-didehydro-L-norvalinamide | 150214-44-1

• 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-<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>-4,5-didehydro-L-norvalinamide
• CAS: 150214-44-1
• 化学式: C₁₉H₃₆N₂O₃
• 分子量: 340.506
• InChiKey: HHMRIXBAXXFDTO-XLAORIBOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.11
• 重原子数：
  24.0
• 可旋转键数：
  10.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  95.58
• 氢给体数：
  4.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  N-<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>-4,5-didehydro-L-norvalinamide 、 2,2-Dimethyl-3-(morpholine-4-carbonyl)-cyclopropanecarboxylic acid 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以32%的产率得到2,2-Dimethyl-3-(morpholine-4-carbonyl)-cyclopropanecarboxylic acid [(S)-1-((1S,2R,3S)-1-cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexylcarbamoyl)-but-3-enyl]-amide
  参考文献：
  名称：

  Design and Synthesis of Renin Inhibitors: Incorporation of Transition-State Isostere Side Chains That Span from the S1 to the S3 Binding Pockets and Examination of P3-Modified Renin Inhibitors

  摘要：

  A series of renin inhibitors were designed to examine the topography of the contiguous binding pocket of renin that is normally occupied by the P1 and P3 side chains. Molecular modeling suggested that extending the P1 hydrophobic side chain into the adjacent hydrophobic S3 enzyme pocket was feasible. Novel transition state isosteres with modified P1-->P3 side chains were synthesized and provided enhanced binding affinity when incorporated into renin inhibitors in which the P3 Phe was substituted by Gly. In a complementary approach, the binding affinities of a variety of P3-P4-modified peptidomimetic renin inhibitors that lacked substantial hydrophobic side chains at these sites were measured.

  DOI：

  10.1021/jm00015a012
• 作为产物：
  描述：

  (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane 在 盐酸 、 碳酸氢钠 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 N-<1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl>-4,5-didehydro-L-norvalinamide
  参考文献：
  名称：

  Design and Synthesis of Renin Inhibitors: Incorporation of Transition-State Isostere Side Chains That Span from the S1 to the S3 Binding Pockets and Examination of P3-Modified Renin Inhibitors

  摘要：

  A series of renin inhibitors were designed to examine the topography of the contiguous binding pocket of renin that is normally occupied by the P1 and P3 side chains. Molecular modeling suggested that extending the P1 hydrophobic side chain into the adjacent hydrophobic S3 enzyme pocket was feasible. Novel transition state isosteres with modified P1-->P3 side chains were synthesized and provided enhanced binding affinity when incorporated into renin inhibitors in which the P3 Phe was substituted by Gly. In a complementary approach, the binding affinities of a variety of P3-P4-modified peptidomimetic renin inhibitors that lacked substantial hydrophobic side chains at these sites were measured.

  DOI：

  10.1021/jm00015a012

文献信息

• Specificity in the binding of inhibitors to the active site of human/primate aspartic proteinases: analysis of P2-P1-P1'-P2' variation
  作者：Chetana M. Rao、Paula E. Scarborough、John Kay、Brian Batley、Stephen Rapundalo、Sylvester Klutchko、Michael D. Taylor、Elizabeth A. Lunney、Christine C. Humblet、Ben M. Dunn

  DOI：10.1021/jm00070a004

  日期：1993.9

  To understand the differences in the binding specificities within the aspartic proteinase family of enzymes, we have carried out studies to determine the inhibition constants of a set of related compounds with various members of the human enzyme family. The inhibition constants (Ki values) were determined by competitive inhibition of the hydrolysis of chromogenic octapeptide substrates in the pH range

  为了了解天冬氨酸蛋白酶家族中酶结合特异性的差异，我们进行了研究以确定一组相关化合物与人类酶家族中各种成员的抑制常数。通过竞争性抑制发色八肽底物在3-5的pH范围内的水解来确定抑制常数（Ki值）。为了比较，在pH 6.0下通过RIA研究了猴肾素的抑制。所有抑制剂均基于4-（吗啉基磺酰基）-L-Phe-P2-（环己基）Ala psi [等排酮-P1'-P2'的一般结构。可裂解肽键的等排取代包括二氟羟基乙烯，1，2-二醇，1，3-二醇和二氟酮。P2中的侧链取代基包括氢，烯丙基，乙硫基，（甲氧羰基）甲基，N-甲基硫脲基丁基，咪唑基甲基和4-氨基-2-噻唑基甲基。我们的测量结果确定了有效的和选择性的抑制剂，可用于评估该家族所选酶之间特异性的差异。