2-(ethylamino)-6-(3-(4-(trifluoromethoxy)phenyl)propanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-carboxamide | 1412452-70-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2-(ethylamino)-6-(3-(4-(trifluoromethoxy)phenyl)propanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-carboxamide
• 英文别名: 2-(ethylamino)-6-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide
• CAS: 1412452-70-0
• 化学式: C₂₀H₂₂F₃N₅O₃
• 分子量: 437.422
• InChiKey: RJTJMAVCPOTSLB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  在 三乙基硅烷 、 palladium 10% on activated carbon 作用下， 以 甲醇 为溶剂， 生成 2-(ethylamino)-6-(3-(4-(trifluoromethoxy)phenyl)propanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-carboxamide
  参考文献：
  名称：

  Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

  摘要：

  Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.

  DOI：

  10.1021/ml300277t

文献信息

• BILE ACID ANALOG TGR5 AGONISTS
  申请人：City of Hope

  公开号：US20140206657A1

  公开（公告）日：2014-07-24

  Provided herein are bile acid analogues and derivatives, methods of synthesizing bile acid analogues and derivatives and their use in treating diabetes and liver disease.

  本文提供了胆酸类似物和衍生物，合成胆酸类似物和衍生物的方法以及它们在治疗糖尿病和肝病中的应用。
• COMPOSITIONS AND METHODS FOR THE TREATMENT OF LIVER DISORDERS
  申请人：Viking Therapeutics, Inc.

  公开号：US20220016136A1

  公开（公告）日：2022-01-20

  The present disclosure is directed toward the use of thyroid receptor agonists of pharmaceutically acceptable salts thereof, in combination with a second pharmaceutical agent for preventing, treating, or ameliorating fatty liver diseases such as steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
• Identification of Tetrahydropyrido[4,3-<i>d</i>]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists
  作者：David W. Piotrowski、Kentaro Futatsugi、Joseph S. Warmus、Suvi T. M. Orr、Kevin D. Freeman-Cook、Allyn T. Londregan、Liuqing Wei、Sandra M. Jennings、Michael Herr、Steven B. Coffey、Wenhua Jiao、Gregory Storer、David Hepworth、Jian Wang、Sophie Y. Lavergne、Janice E. Chin、John R. Hadcock、Martin B. Brenner、Angela C. Wolford、Ann M. Janssen、Nicole S. Roush、Joanne Buxton、Terri Hinchey、Amit S. Kalgutkar、Raman Sharma、Declan A. Flynn

  DOI：10.1021/ml300277t

  日期：2013.1.10

  Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.