6-(5-chloropyridin-2-yl)-3-[4-(3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one | 1221419-66-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 6-(5-chloropyridin-2-yl)-3-[4-(3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one
• 英文别名: 6-(5-chloropyridin-2-yl)-3-[4-[(3R)-3-hydroxypyrrolidin-1-yl]-3-methoxyphenyl]pyrrolo[2,1-f][1,2,4]triazin-4-one
• CAS: 1221419-66-4
• 化学式: C₂₂H₂₀ClN₅O₃
• 分子量: 437.885
• InChiKey: SKYSAAKSQGUHJV-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  83.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-氨基-4-溴-1H-吡咯-2-羧酸甲酯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 、 potassium carbonate 、 1-羟基苯并三唑 、 溶剂黄146 、 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 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 5.25h， 生成 6-(5-chloropyridin-2-yl)-3-[4-(3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one
  参考文献：
  名称：

  Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies

  摘要：

  Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 K-i = 1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.09.018

文献信息

• AZOLOTRIAZINONE MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS
  申请人：Devasthale Pratik

  公开号：US20110218185A1

  公开（公告）日：2011-09-08

  The present application provides compounds that are useful as MCHR1 antagonists, especially for the treatment of obesity, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I wherein the variables are defined herein.

  本申请提供了一些化合物，它们可用作MCHR1拮抗剂，特别适用于治疗肥胖症，包括所有立体异构体、溶剂合物、前药和药学上可接受的I式形式，其中变量在此定义。
• US8580959B2
  申请人：——

  公开号：US8580959B2

  公开（公告）日：2013-11-12
• US8754211B2
  申请人：——

  公开号：US8754211B2

  公开（公告）日：2014-06-17
• Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies
  作者：Pratik Devasthale、Wei Wang、James Mignone、Kishore Renduchintala、Sridhar Radhakrishnan、Jayanthi Dhanapal、Jagannath Selvaraj、Rajesh Kuppusamy、Mary Ann Pelleymounter、Daniel Longhi、Ning Huang、Neil Flynn、Anthony V. Azzara、Kenneth Rohrbach、James Devenny、Suzanne Rooney、Michael Thomas、Susan Glick、Helen Godonis、Susan Harvey、Mary Jane Cullen、Hongwei Zhang、Christian Caporuscio、Paul Stetsko、Mary Grubb、Christine Huang、Lisa Zhang、Chris Freeden、Brian J. Murphy、Jeffrey A. Robl、William N. Washburn

  DOI：10.1016/j.bmcl.2015.09.018

  日期：2015.10

  Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 K-i = 1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible. (C) 2015 Elsevier Ltd. All rights reserved.