1,1-dimethylethyl [(1S)-2-(3-chlorophenyl)-1-(hydroxymethyl)ethyI]carbamate | 944470-59-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1,1-dimethylethyl [(1S)-2-(3-chlorophenyl)-1-(hydroxymethyl)ethyI]carbamate
• 英文别名: tert-butyl [(1S)-1-(3-chlorobenzyl)-2-hydroxyethyl]carbamate；tert-butyl N-[(2S)-1-(3-chlorophenyl)-3-hydroxypropan-2-yl]carbamate
• CAS: 944470-59-1
• 化学式: C₁₄H₂₀ClNO₃
• 分子量: 285.771
• InChiKey: BGKJNWVSAGMOLA-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl [(1S)-2-(3-chlorophenyl)-1-(hydroxymethyl)ethyI]carbamate 在 tris(dibenzylideneacetone)dipalladium (0) 、 三(邻甲基苯基)磷 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1S)-1-(3-chlorobenzyl)-2-[5-(3-methyl-1H-indazol-5-yl)pyridin-3-yloxy]-ethylamine bistrifluoroacetate
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019

文献信息

• [EN] INHIBITORS OF AKT ACTIVITY<br/>[FR] INHIBITEURS DE L'ACTIVITÉ D'AKT
  申请人：SMITHKLINE BEECHAM CORP

  公开号：WO2009032653A1

  公开（公告）日：2009-03-12

  Invented are novel substituted pyridine compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

  本发明涉及一种新型取代吡啶化合物，其作为蛋白激酶B活性抑制剂和治疗癌症和关节炎的用途。
• The identification of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamines as potent inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1)
  作者：Thomas Nittoli、Russell G. Dushin、Charles Ingalls、Katherine Cheung、M. Brawner Floyd、Heidi Fraser、Andrea Olland、Yongbo Hu、George Grosu、Xin Han

  DOI：10.1016/j.ejmech.2009.12.036

  日期：2010.4

  A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c] [2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer. (C) 2009 Elsevier Masson SAS. All rights reserved.