7-(4-chloro-3-methoxyphenyl)-2-[[(2-chloro-6-fluorophenyl)methyl]sulfanyl]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-1,3-benzodiazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 7-(4-chloro-3-methoxyphenyl)-2-[[(2-chloro-6-fluorophenyl)methyl]sulfanyl]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-1,3-benzodiazole
• 英文别名: 2-[(2-Chloro-6-fluorophenyl)methylsulfanyl]-7-(4-chloro-3-methoxyphenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzimidazole；2-[(2-chloro-6-fluorophenyl)methylsulfanyl]-7-(4-chloro-3-methoxyphenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzimidazole
• 化学式: C₂₇H₂₂Cl₃FN₂OS
• 分子量: 547.908
• InChiKey: AQLQSVMBTLUCHI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  52.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  在 caesium carbonate 、 溶剂黄146 作用下， 以 丙酮 为溶剂， 反应 3.0h， 生成 7-(4-chloro-3-methoxyphenyl)-2-[[(2-chloro-6-fluorophenyl)methyl]sulfanyl]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-1,3-benzodiazole
  参考文献：
  名称：

  Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes

  摘要：

  We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGRS. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGRS (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)(0-120 min) in oral glucose tolerance tests (OGTT).

  DOI：

  10.1021/acsmedchemlett.7b00116

文献信息

• Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes
  作者：Xuqing Zhang、Mark Wall、Zhihua Sui、Jack Kauffman、Cuifen Hou、Cailin Chen、Fuyong Du、Thomas Kirchner、Yin Liang、Dana L. Johnson、William V. Murray、Keith Demarest

  DOI：10.1021/acsmedchemlett.7b00116

  日期：2017.5.11

  We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGRS. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGRS (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)(0-120 min) in oral glucose tolerance tests (OGTT).