(R)-tert-butyl 4-(2-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimetyloxazolidine-3-carboxylate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (R)-tert-butyl 4-(2-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimetyloxazolidine-3-carboxylate
• 英文别名: tert-butyl (4R)-2,2,4-trimethyl-4-[[2-oxo-2-[4-[(4-phenylphenyl)methoxy]-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-1,3-oxazolidine-3-carboxylate
• 化学式: C₃₄H₃₇F₃N₂O₆
• 分子量: 626.673
• InChiKey: YEBQJZAVNVYQCR-MGBGTMOVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  45
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  94.2
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl 4-(2-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimetyloxazolidine-3-carboxylate 在 六氯乙烷 、 三乙胺 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以79%的产率得到(S)-tert-butyl 4-(5-(4-([1,1'-biphenyl]-4-ylmethoxy)-3-(trifluoromethyl)phenyl)oxazol-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
• 作为产物：
  描述：

  联苯-4-甲醇 在 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 为溶剂， 反应 7.08h， 生成 (R)-tert-butyl 4-(2-(4-(biphenyl-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimetyloxazolidine-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