1-[(1R)-1-{3-[(tert-butyldiphenylsilyl)oxy]-5-fluorophenyl}-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-phenylethyl]-3-(2,2,2-trifluoroethyl)urea | 939398-86-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 1-[(1R)-1-{3-[(tert-butyldiphenylsilyl)oxy]-5-fluorophenyl}-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-phenylethyl]-3-(2,2,2-trifluoroethyl)urea
• 英文别名: (R)-1-(1-(3-(tert-butyldiphenylsilyloxy)-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea；1-[(1R)-1-[3-[tert-butyl(diphenyl)silyl]oxy-5-fluorophenyl]-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-phenylethyl]-3-(2,2,2-trifluoroethyl)urea
• CAS: 939398-86-4
• 化学式: C₄₀H₃₆F₈N₂O₂Si
• 分子量: 756.811
• InChiKey: KIUHZKSXSSJJGH-KXQOOQHDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.27
• 重原子数：
  53
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  50.4
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  1-[(1R)-1-{3-[(tert-butyldiphenylsilyl)oxy]-5-fluorophenyl}-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-phenylethyl]-3-(2,2,2-trifluoroethyl)urea 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 0.83h， 以77%的产率得到1-[(1R)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl]-3-(2,2,2-trifluoroethyl)urea
  参考文献：
  名称：

  Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)

  摘要：

  Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.

  DOI：

  10.1021/acs.jmedchem.5b01363
• 作为产物：
  描述：

  2,2,2-三氟乙基胺 、 在 1-甲基吡咯烷 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 0.33h， 以132 mg的产率得到1-[(1R)-1-{3-[(tert-butyldiphenylsilyl)oxy]-5-fluorophenyl}-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-phenylethyl]-3-(2,2,2-trifluoroethyl)urea
  参考文献：
  名称：

  Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)

  摘要：

  Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.

  DOI：

  10.1021/acs.jmedchem.5b01363

文献信息

• HETEROCYCLIC CETP INHIBITORS
  申请人：Salvati E. Mark

  公开号：US20070135631A1

  公开（公告）日：2007-06-14

  Compounds of formula Ia and Ib wherein A, B, C and R 1 are described herein.

  公式Ia和Ib的化合物，其中A、B、C和R1如下所述。
• Heterocyclic CETP inhibitors
  申请人：Bristol-Myers Squibb Company

  公开号：US07790770B2

  公开（公告）日：2010-09-07

  Compounds of formula Ia and Ib wherein A, B, C and R1 are described herein.

  Ia和Ib的化合物，其中A、B、C和R1如下所述。
• WO2007/62308
  申请人：——

  公开号：——

  公开（公告）日：——
• Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>-[(1<i>R</i>)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311)
  作者：Jennifer X. Qiao、Tammy C. Wang、Leonard P. Adam、Alice Ye A. Chen、David S. Taylor、Richard Z. Yang、Shaobin Zhuang、Paul G. Sleph、Julia P. Li、Danshi Li、Xiaohong Yin、Ming Chang、Xue-Qing Chen、Hong Shen、Jianqing Li、Daniel Smith、Dauh-Rurng Wu、Leslie Leith、Lalgudi S. Harikrishnan、Muthoni G. Kamau、Michael M. Miller、Donna Bilder、Richard Rampulla、Yi-Xin Li、Carrie Xu、R. Michael Lawrence、Michael A. Poss、Paul Levesque、David A. Gordon、Christine S. Huang、Heather J. Finlay、Ruth R. Wexler、Mark E. Salvati

  DOI：10.1021/acs.jmedchem.5b01363

  日期：2015.11.25

  Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.