6-Tert-butyl 4-ethyl 2-hydroxy-7,8-dihydropyrido[4,3-D]pyrimidine-4,6(5H)-dicarboxylate | 1412452-82-4

• 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: 6-Tert-butyl 4-ethyl 2-hydroxy-7,8-dihydropyrido[4,3-D]pyrimidine-4,6(5H)-dicarboxylate
• 英文别名: 6-O-tert-butyl 4-O-ethyl 2-oxo-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-4,6-dicarboxylate
• CAS: 1412452-82-4
• 化学式: C₁₅H₂₁N₃O₅
• 分子量: 323.349
• InChiKey: MZLQNJKUOXNGQA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  97.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-Tert-butyl 4-ethyl 2-hydroxy-7,8-dihydropyrido[4,3-D]pyrimidine-4,6(5H)-dicarboxylate 在 [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride 、 氨 、 三氟乙酸 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 58.0h， 生成
  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
• 作为产物：
  描述：

  1-N-Boc-4-氧代-3-哌啶羧酸乙酯 、 尿素 在 溶剂黄146 作用下， 反应 18.0h， 以150 g的产率得到6-Tert-butyl 4-ethyl 2-hydroxy-7,8-dihydropyrido[4,3-D]pyrimidine-4,6(5H)-dicarboxylate
  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

• 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.