N-{(1S)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanecarboxamide | 1239893-92-5

• 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: N-{(1S)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanecarboxamide
• 英文别名: N-[(2S)-1-(3-amino-8-azabicyclo[3.2.1]octan-8-yl)-3-(2,4-dichlorophenyl)-1-oxopropan-2-yl]-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide
• CAS: 1239893-92-5
• 化学式: C₂₆H₂₇Cl₄N₃O₂
• 分子量: 555.331
• InChiKey: FTCUCNANDOCSHQ-GAXRGCCTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  75.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 73.0h， 生成 N-{(1S)-2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-[(2,4-dichlorophenyl)methyl]-2-oxoethyl}-1-(2,4-dichlorophenyl)cyclopropanecarboxamide
  参考文献：
  名称：

  Discovery and Characterization of an Inhibitor of Glucosylceramide Synthase

  摘要：

  Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC50 of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.

  DOI：

  10.1021/jm300122u

文献信息

• [EN] INHIBITORS OF GLUCOSYLCERAMIDE SYNTHASE<br/>[FR] INHIBITEURS DE LA GLUCOSYLCÉRAMIDE SYNTHASE
  申请人：EXELIXIS INC

  公开号：WO2010091164A1

  公开（公告）日：2010-08-12

  The present invention comprises glucosylceramide synthase (GCS) modulators of following structural formula (I); wherein R1, A, L, R2, R3, and m are defined herein, as well as N-oxides of them and pharmaceutically acceptable salts thereof, and methods of making said compounds. The invention further comprises compositions comprising the compounds, N-oxides, and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which GCS is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which GCS is a mediator or is implicated.
• Discovery and Characterization of an Inhibitor of Glucosylceramide Synthase
  作者：Steven Richards、Christopher J. Larson、Elena S. Koltun、Art Hanel、Vicky Chan、Jason Nachtigall、Amanda Harrison、Naing Aay、Hongwang Du、Arlyn Arcalas、Adam Galan、Jeff Zhang、Wentao Zhang、Kwang-Ai Won、Danny Tam、Fawn Qian、Tao Wang、Patricia Finn、Kathy Ogilvie、Jon Rosen、Ron Aoyama、Artur Plonowski、Belinda Cancilla、Frauke Bentzien、Michael Yakes、Raju Mohan、Peter Lamb、John Nuss、Patrick Kearney

  DOI：10.1021/jm300122u

  日期：2012.5.10

  Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC50 of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.