(R)-tert-butyl-4-(5-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (R)-tert-butyl-4-(5-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate
• 英文别名: tert-butyl (4R)-2,2,4-trimethyl-4-[5-[4-[(4-phenylphenyl)methoxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-1,3-oxazolidine-3-carboxylate
• 化学式: C₃₄H₃₅F₃N₂O₄S
• 分子量: 624.724
• InChiKey: CSWZUVORJIVWIJ-MGBGTMOVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  89.1
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl-4-(5-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate 在 对甲苯磺酸一水合物 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以60%的产率得到(S)-2-amino-2-(5-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol
  参考文献：
  名称：

  Discovery of Clinical Candidate GSK1842799 As a Selective S1P₁ Receptor Agonist (Prodrug) for Multiple Sclerosis

  摘要：

  To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P(1) modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl) -1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P(1) agonist activity with >1000x selectivity over S1P(3). The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.

  DOI：

  10.1021/ml400194r
• 作为产物：
  描述：

  联苯-4-甲醇 在 劳森试剂 、 盐酸 、 sodium azide 、 palladium 10% on activated carbon 、 potassium tert-butylate 、 氢气 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 copper(ll) bromide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.58h， 生成 (R)-tert-butyl-4-(5-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate
  参考文献：
  名称：

  Discovery of Clinical Candidate GSK1842799 As a Selective S1P₁ Receptor Agonist (Prodrug) for Multiple Sclerosis

  摘要：

  To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P(1) modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl) -1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P(1) agonist activity with >1000x selectivity over S1P(3). The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.

  DOI：

  10.1021/ml400194r

文献信息

• Methods and compositions for modulating sphingosine-1-phosphate (S1P) receptor activity
  申请人：Evindar Ghotas

  公开号：US20060223866A1

  公开（公告）日：2006-10-05

  The present invention relates to compounds which modulate the activity of the S1P1 receptor, the use of these compounds for treating conditions associated with signaling through the S1P1 receptor, and pharmaceutical compositions comprising these compounds.

  本发明涉及调节S1P1受体活性的化合物，使用这些化合物治疗与S1P1受体信号传导相关的疾病，并包括这些化合物的制药组合物。
• Discovery of Clinical Candidate GSK1842799 As a Selective S1P₁ Receptor Agonist (Prodrug) for Multiple Sclerosis
  作者：Hongfeng Deng、Sylvie G. Bernier、Elisabeth Doyle、Jeanine Lorusso、Barry A. Morgan、William F. Westlin、Ghotas Evindar

  DOI：10.1021/ml400194r

  日期：2013.10.10

  To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P(1) modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl) -1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P(1) agonist activity with >1000x selectivity over S1P(3). The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.