5-(3-(7-(2,2-dimethyl-1,3-dioxan-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile | 1333996-64-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-(3-(7-(2,2-dimethyl-1,3-dioxan-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile
• CAS: 1333996-64-7
• 化学式: C₂₇H₃₁N₅O₄
• 分子量: 489.574
• InChiKey: JSWLHLXRMYDEKZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.28
• 重原子数：
  36.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  106.53
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  5-(3-(7-(2,2-dimethyl-1,3-dioxan-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 在 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.5h， 以249 mg的产率得到5-(3-(7-(1,3-dihydroxypropan-2-yl)-4-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride
  参考文献：
  名称：

  Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose

  摘要：

  2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RAMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P5 agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (< 1 mg p.o. once daily).

  DOI：

  10.1021/jm200609t
• 作为产物：
  描述：

  tert-butyl 3-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-4-methyl-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 18.75h， 生成 5-(3-(7-(2,2-dimethyl-1,3-dioxan-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile
  参考文献：
  名称：

  Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose

  摘要：

  2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RAMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P5 agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (< 1 mg p.o. once daily).

  DOI：

  10.1021/jm200609t

文献信息

• 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.