methyl (2S)-2-[4-chloro-6-(3,4-dimethylphenyl)-2,5-dimethylpyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetate | 1256254-52-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: methyl (2S)-2-[4-chloro-6-(3,4-dimethylphenyl)-2,5-dimethylpyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetate
• CAS: 1256254-52-0
• 化学式: C₂₂H₂₈ClNO₃
• 分子量: 389.922
• InChiKey: FIMAMKFAXQWZFA-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  48.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (2S)-2-[4-chloro-6-(3,4-dimethylphenyl)-2,5-dimethylpyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetate 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 、 水 为溶剂， 生成 (2S)-2-tert-butoxy-2-[4-(4-chlorophenyl)-6-(3,4-dimethylphenyl)-2,5-dimethyl-3-pyridyl]acetic acid
  参考文献：
  名称：

  Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

  摘要：

  A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having 1 T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.

  DOI：

  10.1021/ml500110j
• 作为产物：
  描述：

  methyl (2S)-2-(4,6-dichloro-2,5-dimethylpyridin-3-yl)-2-hydroxyacetate 在 bis-triphenylphosphine-palladium(II) chloride 高氯酸 、 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 methyl (2S)-2-[4-chloro-6-(3,4-dimethylphenyl)-2,5-dimethylpyridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]acetate
  参考文献：
  名称：

  [EN] INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
  [FR] INHIBITEURS DE LA REPLICATION DU VIRUS DE L'IMMUNODEFICIENCE HUMAINE

  摘要：

  式I中的化合物，其中a、R1、R2、R3、R4、R5和R6如本文所定义，可用作HIV复制抑制剂。

  公开号：

  WO2010130034A1

文献信息

• [EN] INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION<br/>[FR] INHIBITEURS DE LA REPLICATION DU VIRUS DE L'IMMUNODEFICIENCE HUMAINE
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2010130034A1

  公开（公告）日：2010-11-18

  Compounds of formula I wherein a, R1, R2, R3, R4, R5 and R6 are defined herein, are useful as inhibitors of HIV replication.

  式I中的化合物，其中a、R1、R2、R3、R4、R5和R6如本文所定义，可用作HIV复制抑制剂。
• INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
  申请人：BOEHRINGER INGELHEIM INTERNATIONAL GMBH

  公开号：EP2429993B1

  公开（公告）日：2015-01-21
• US8338441B2
  申请人：——

  公开号：US8338441B2

  公开（公告）日：2012-12-25
• US8841331B2
  申请人：——

  公开号：US8841331B2

  公开（公告）日：2014-09-23
• Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV
  作者：Lee D. Fader、Rebekah Carson、Sébastien Morin、François Bilodeau、Catherine Chabot、Ted Halmos、Murray D. Bailey、Stephen H. Kawai、René Coulombe、Steven Laplante、Kevork Mekhssian、Araz Jakalian、Michel Garneau、Jianmin Duan、Stephen W. Mason、Bruno Simoneau、Craig Fenwick、Youla Tsantrizos、Christiane Yoakim

  DOI：10.1021/ml500110j

  日期：2014.6.12

  A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having 1 T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.