(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(5-amino-pent-1-yl)-amine (Hydrobromide Salt)

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(5-amino-pent-1-yl)-amine (Hydrobromide Salt)
• 英文别名: N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)pentane-1,5-diamine;hydrobromide
• 化学式: BrH*C₂₂H₂₉N₅
• 分子量: 444.418
• InChiKey: YDRLZPMFMFJBBB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.54
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  70.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  N1-(1H-benzo[d]imidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)pentane-1,5-diamine 在 氢溴酸 、 溶剂黄146 作用下， 以76%的产率得到(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(5-amino-pent-1-yl)-amine (Hydrobromide Salt)
  参考文献：
  名称：

  Discovery of Novel Small Molecule Orally Bioavailable C−X−C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication

  摘要：

  The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure activity relationship (SA R) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-Amethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 (125)I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 mu M. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.

  DOI：

  10.1021/jm100073m

文献信息

• Discovery of Novel Small Molecule Orally Bioavailable C−X−C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication
  作者：Renato T. Skerlj、Gary J. Bridger、Al Kaller、Ernest J. McEachern、Jason B. Crawford、Yuanxi Zhou、Bem Atsma、Jonathon Langille、Susan Nan、Duane Veale、Trevor Wilson、Curtis Harwig、Sigrid Hatse、Katrien Princen、Erik De Clercq、Dominique Schols

  DOI：10.1021/jm100073m

  日期：2010.4.22

  The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure activity relationship (SA R) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-Amethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 (125)I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 mu M. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.