5-(3-(2-(1,3-dihydroxypropan-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile | 1333995-67-7

• 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-(2-(1,3-dihydroxypropan-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile
• 英文别名: 5-[3-[2-(1,3-dihydroxypropan-2-yl)-3,4-dihydro-1H-isoquinolin-6-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile
• CAS: 1333995-67-7
• 化学式: C₂₄H₂₆N₄O₄
• 分子量: 434.495
• InChiKey: CRBLLNHYYCHVFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-(3-(2-(1,3-dihydroxypropan-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 在 盐酸 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 0.08h， 以85%的产率得到5-(3-(2-(1,3-dihydroxypropan-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-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：

  3-氰基-4-异丙氧基苯甲酸 在 吡啶 、 盐酸 、 草酰氯 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 42.66h， 生成 5-(3-(2-(1,3-dihydroxypropan-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-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

• Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose
  作者：Emmanuel H. Demont、Sandra Arpino、Rino A. Bit、Colin A. Campbell、Nigel Deeks、Sapna Desai、Simon J. Dowell、Pam Gaskin、James R. J. Gray、Lee A. Harrison、Andrea Haynes、Tom D. Heightman、Duncan S. Holmes、Philip G. Humphreys、Umesh Kumar、Mary A. Morse、Greg J. Osborne、Terry Panchal、Karen L. Philpott、Simon Taylor、Robert Watson、Robert Willis、Jason Witherington

  DOI：10.1021/jm200609t

  日期：2011.10.13

  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).