5-(5-(2-(2,2-dimethyl-1,3-dioxan-5-yl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile | 1258856-61-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 5-(5-(2-(2,2-dimethyl-1,3-dioxan-5-yl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile
• 英文别名: 5-{5-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl]-1,3,4-thiadiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile；5-[5-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-5-methyl-3,4-dihydro-1H-isoquinolin-6-yl]-1,3,4-thiadiazol-2-yl]-2-propan-2-yloxybenzonitrile
• CAS: 1258856-61-9
• 化学式: C₂₈H₃₂N₄O₃S
• 分子量: 504.653
• InChiKey: CFHDGUFJGTXWMP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  109
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-(5-(2-(2,2-dimethyl-1,3-dioxan-5-yl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 在 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 2.0h， 以60%的产率得到5-(5-(2-(1,3-dihydroxypropan-2-yl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride
  参考文献：
  名称：

  Navigating CYP1A Induction and Arylhydrocarbon Receptor Agonism in Drug Discovery. A Case History with S1P₁ Agonists

  摘要：

  This article describes the finding of substantial upregulation of mRNA and enzymes of the cytochrome P450 1A family during a lead optimization campaign for small molecule S1P(1). agonists. Fold changes in mRNA up to 10 000-fold for CYP1A1 in vivo in rat and cynomolgus monkey and up to 45-fold for GYP1A1 and GYP1A2 in vitro in rat and human hepatocytes were observed. Challenges observed with correlating induction in vitro and induction in vivo resulted in the implementation of a short, 4 day in vivo screening study in the rat which successfully identified noninducers. Subtle structure-activity relationships in this series of S1P(1) agonists are described extending beyond planarity and lipophilicity, and the impact and considerations of AhR and CYPIA induction in the context of drug development are discussed.

  DOI：

  10.1021/acs.jmedchem.5b01102
• 作为产物：
  描述：

  邻羟基苯甲腈 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 N-碘代丁二酰亚胺 、 三氟甲磺酸 、 potassium acetate 、 三乙酰氧基硼氢化钠 、 sodium carbonate 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 24.75h， 生成 5-(5-(2-(2,2-dimethyl-1,3-dioxan-5-yl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile
  参考文献：
  名称：

  [EN] S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
  [FR] AGONISTES DE S1P1 COMPRENANT UN CYCLE AZOTÉ BICYCLIQUE

  摘要：

  本发明涉及具有S1P1激动剂活性的式(I)新化合物，其制备方法，包含它们的药物组合物及其用于治疗各种疾病的应用。

  公开号：

  WO2010146105A1

文献信息

• S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
  申请人：Bailey James Matthew

  公开号：US20120101083A1

  公开（公告）日：2012-04-26

  The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有S1P1激动剂活性的公式（I）的新化合物，其制备过程，含有它们的药物组合物以及它们在治疗各种疾病中的应用。
• Navigating CYP1A Induction and Arylhydrocarbon Receptor Agonism in Drug Discovery. A Case History with S1P₁ Agonists
  作者：Simon J. Taylor、Emmanuel H. Demont、James Gray、Nigel Deeks、Aarti Patel、Dung Nguyen、Maxine Taylor、Steve Hood、Robert J. Watson、Rino A. Bit、Fiona McClure、Holly Ashall、Jason Witherington

  DOI：10.1021/acs.jmedchem.5b01102

  日期：2015.10.22

  This article describes the finding of substantial upregulation of mRNA and enzymes of the cytochrome P450 1A family during a lead optimization campaign for small molecule S1P(1). agonists. Fold changes in mRNA up to 10 000-fold for CYP1A1 in vivo in rat and cynomolgus monkey and up to 45-fold for GYP1A1 and GYP1A2 in vitro in rat and human hepatocytes were observed. Challenges observed with correlating induction in vitro and induction in vivo resulted in the implementation of a short, 4 day in vivo screening study in the rat which successfully identified noninducers. Subtle structure-activity relationships in this series of S1P(1) agonists are described extending beyond planarity and lipophilicity, and the impact and considerations of AhR and CYPIA induction in the context of drug development are discussed.
• [EN] S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING<br/>[FR] AGONISTES DE S1P1 COMPRENANT UN CYCLE AZOTÉ BICYCLIQUE
  申请人：GLAXO GROUP LTD

  公开号：WO2010146105A1

  公开（公告）日：2010-12-23

  The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有S1P1激动剂活性的式(I)新化合物，其制备方法，包含它们的药物组合物及其用于治疗各种疾病的应用。