N1-(4,4-difluorocyclohexyl)-2,2-dimethyl-N4-(((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)-N4-((S)-5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine

• 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: N1-(4,4-difluorocyclohexyl)-2,2-dimethyl-N4-(((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)-N4-((S)-5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine
• 英文别名: N-(4,4-difluorocyclohexyl)-2,2-dimethyl-N'-[[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl]-N'-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine
• 化学式: C₃₁H₄₄F₂N₄
• 分子量: 510.714
• InChiKey: BCTNZAWHTKKRHH-IZLXSDGUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  40.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,2-二甲基丁烷-1,4-二醇 在 咪唑 、 盐酸 、 偶氮二甲酸二异丙酯 、 三氧化硫吡啶 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 三乙胺 、 三苯基膦 、 三氟乙酸 、 肼 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 104.5h， 生成 N1-(4,4-difluorocyclohexyl)-2,2-dimethyl-N4-(((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)-N4-((S)-5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine
  参考文献：
  名称：

  Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties

  摘要：

  CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by >= 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4(+) tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4(+) immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR44(+) cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.

  DOI：

  10.1021/acs.jmedchem.7b01420

文献信息

• Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
  作者：Eric J. Miller、Edgars Jecs、Valarie M. Truax、Brooke M. Katzman、Yesim A. Tahirovic、Robert J. Wilson、Katie M. Kuo、Michelle B. Kim、Huy H. Nguyen、Manohar T. Saindane、Huanyu Zhao、Tao Wang、Chi S. Sum、Mary E. Cvijic、Gretchen M. Schroeder、Lawrence J. Wilson、Dennis C. Liotta

  DOI：10.1021/acs.jmedchem.7b01420

  日期：2018.2.8

  CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by >= 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4(+) tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4(+) immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR44(+) cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.