2-[1-(4-chlorophenyl)-2-methylpropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid | 1239150-04-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-[1-(4-chlorophenyl)-2-methylpropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid
• CAS: 1239150-04-9
• 化学式: C₂₁H₁₇ClF₃NO₃
• 分子量: 423.819
• InChiKey: ZGZLDIYOVSIDTR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  70.4
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  7-三氟甲基靛红 、 3-(4-chlorophenyl)-1-hydroxy-4-methylpentan-2-one 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 以10.8%的产率得到2-[1-(4-chlorophenyl)-2-methylpropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid
  参考文献：
  名称：

  Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic Acid (PSI-421), a P-Selectin Inhibitor with Improved Pharmacokinetic Properties and Oral Efficacy in Models of Vascular Injury

  摘要：

  Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure activity-studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.

  DOI：

  10.1021/jm9013696

文献信息

• Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic Acid (PSI-421), a P-Selectin Inhibitor with Improved Pharmacokinetic Properties and Oral Efficacy in Models of Vascular Injury
  作者：Adrian Huang、Alessandro Moretto、Kristin Janz、Michael Lowe、Patricia W. Bedard、Steve Tam、Li Di、Valerie Clerin、Natalia Sushkova、Boris Tchernychev、Desiree H. H. Tsao、James C. Keith、Gray D. Shaw、Robert G. Schaub、Qin Wang、Neelu Kaila

  DOI：10.1021/jm9013696

  日期：2010.8.26

  Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure activity-studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.