4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-[(1S,2R,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone | 1297140-12-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-[(1S,2R,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
• 英文别名: 4-[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbonyl]-1-[(1S,3S,4R,5S)-4-hydroxy-3-bicyclo[3.1.0]hexanyl]piperazin-2-one；4-[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbonyl]-1-[(1S,2R,3S,5S)-2-hydroxy-3-bicyclo[3.1.0]hexanyl]piperazin-2-one
• CAS: 1297140-12-5
• 化学式: C₂₂H₂₂ClF₃N₄O₃
• 分子量: 482.89
• InChiKey: MVIDQQZWMHRXFV-FCMVICDYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  78.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-三氟甲基吡啶 在 吡啶 、 盐酸 、 甲醇 、 selenium(IV) oxide 、 potassium phosphate 、 N-氯代丁二酰亚胺 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 (1,5-cyclooctadiene)(methoxy)iridium(I) dimer 、 二氧化碳 、 硫酸 、 水 、 双氧水 、 diethylzinc 、 potassium carbonate 、 溶剂黄146 、 1-丙基磷酸酐 、 N,N-二异丙基乙胺 、 三氟乙酸 、 4,4'-二叔丁基-2,2'-二吡啶 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 105.0 ℃ 、14.0 MPa 条件下， 反应 171.88h， 生成 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-[(1S,2R,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
  参考文献：
  名称：

  Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein

  摘要：

  We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead la. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound la was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.

  DOI：

  10.1021/jm400125h

文献信息

• Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein
  作者：John F. Miller、Pek Y. Chong、J. Brad Shotwell、John G. Catalano、Vincent W.-F. Tai、Jing Fang、Anna L. Banka、Christopher D. Roberts、Michael Youngman、Huichang Zhang、Zhiping Xiong、Amanda Mathis、Jeffery J. Pouliot、Robert K. Hamatake、Daniel J. Price、John W. Seal、Lisa L. Stroup、Katrina L. Creech、Luz H. Carballo、Dan Todd、Andrew Spaltenstein、Sylvia Furst、Zhi Hong、Andrew J. Peat

  DOI：10.1021/jm400125h

  日期：2014.3.13

  We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead la. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound la was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.