(S)-2-(3-((S)-1-carboxypentyl)ureido)-6-(4-iodobenzamido)hexanoic acid | 1339952-63-4

• 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: (S)-2-(3-((S)-1-carboxypentyl)ureido)-6-(4-iodobenzamido)hexanoic acid
• 英文别名: (2S)-2-[[(1S)-1-carboxypentyl]carbamoylamino]-6-[(4-iodobenzoyl)amino]hexanoic acid
• CAS: 1339952-63-4
• 化学式: C₂₀H₂₈IN₃O₆
• 分子量: 533.363
• InChiKey: HRAPTOQHTHNTQY-HOTGVXAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  30
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  145
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (S)-2-Amino-6-tert-butoxycarbonylamino-hexanoic acid tert-butyl ester 在 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 (S)-2-(3-((S)-1-carboxypentyl)ureido)-6-(4-iodobenzamido)hexanoic acid
  参考文献：
  名称：

  Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity

  摘要：

  Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.

  DOI：

  10.1021/jm200807m

文献信息

• Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity
  作者：Anna Plechanovová、Youngjoo Byun、Glenda Alquicer、L'ubica Škultétyová、Petra Mlčochová、Adriana Němcová、Hyung-Joon Kim、Michal Navrátil、Ronnie Mease、Jacek Lubkowski、Martin Pomper、Jan Konvalinka、Lubomír Rulíšek、Cyril Bařinka

  DOI：10.1021/jm200807m

  日期：2011.11.10

  Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.