1-(4-(4-phenylbenzyloxy)-3-(trifluoromethyl)phenyl)ethanone | 911412-52-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(4-(4-phenylbenzyloxy)-3-(trifluoromethyl)phenyl)ethanone
• 英文别名: 2-Bromo-1-[4-[(4-phenylphenyl)methoxy]-3-(trifluoromethyl)phenyl]ethanone
• CAS: 911412-52-7
• 化学式: C₂₂H₁₆BrF₃O₂
• 分子量: 449.267
• InChiKey: LEBZHHMLPNNNTI-UHFFFAOYSA-N

物化性质

• 沸点：
  520.2±50.0 °C(predicted)
• 密度：
  1.414±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(4-(4-phenylbenzyloxy)-3-(trifluoromethyl)phenyl)ethanone 在 盐酸 、 sodium azide 、 六氯乙烷 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.33h， 生成 (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 potassium tert-butylate 、 copper(ll) bromide 作用下， 以 四氢呋喃 、 氯仿 、 乙酸乙酯 为溶剂， 反应 3.75h， 生成 1-(4-(4-phenylbenzyloxy)-3-(trifluoromethyl)phenyl)ethanone
  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

• Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists
  作者：Ghotas Evindar、Sylvie G. Bernier、Elisabeth Doyle、Malcolm J. Kavarana、Alexander L. Satz、Jeanine Lorusso、Heather S. Blanchette、Ashis K. Saha、Gerhard Hannig、Barry A. Morgan、William F. Westlin

  DOI：10.1016/j.bmcl.2010.02.098

  日期：2010.4

  In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration. (C) 2010 Elsevier Ltd. All rights reserved.
• Exploring amino acids derivatives as potent, selective, and direct agonists of sphingosine-1-phosphate receptor subtype-1
  作者：Ghotas Evindar、Hongfeng Deng、Sylvie G. Bernier、Elisabeth Doyle、Jeanine Lorusso、Barry A. Morgan、William F. Westlin

  DOI：10.1016/j.bmcl.2012.11.053

  日期：2013.1

  In the quest to discover a potent and selective class of direct agonists to the sphingosine-1-phosphate receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P receptor subtype 1 over 3. (C) 2012 Elsevier Ltd. All rights reserved.
• [EN] METHODS AND COMPOSITIONS FOR MODULATING SPHINGOSINE-1-PHOSPHATE (S1P) RECEPTOR ACTIVITY<br/>[FR] PROCEDES ET COMPOSITIONS PERMETTANT DE MODULER L'ACTIVITE DU RECEPTEUR DU SPHINGOSINE-1-PHOSPHATE (S1P)
  申请人：PRAECIS PHARM INC

  公开号：WO2007092190A2

  公开（公告）日：2007-08-16

  [EN] The present invention relates to compounds which modulate the activity of the SlPl receptor, the use of these compounds for treating conditions associated with signaling through the SlPl receptor, and pharmaceutical compositions comprising these compounds.
  [FR] La présente invention concerne des composés qui modulent l'activité du récepteur du récepteur du SIPI, l'utilisation de ces composés pour traiter des états associés à la signalisation par le récepteur du SIPI et des compositions pharmaceutiques comprenant ces composés.
• 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.