3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)benzoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)benzoic acid
• 英文别名: 3-(5,6-dichloro-1H-benzimidazol-2-yl)benzoic acid
• 化学式: C₁₄H₈Cl₂N₂O₂
• 分子量: 307.136
• InChiKey: BHTFEGRQYBFRQQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  66
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  methyl 3-(5,6-dichloro-1H-benzimidazol-2-yl)benzoate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 以7 mg的产率得到3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)benzoic acid
  参考文献：
  名称：

  Hit-to-Lead Optimization and Discovery of 5-((5-([1,1′-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase

  摘要：

  AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.

  DOI：

  10.1021/acs.jmedchem.7b01344

文献信息

• Hit-to-Lead Optimization and Discovery of 5-((5-([1,1′-Biphenyl]-4-yl)-6-chloro-1<i>H</i>-benzo[<i>d</i>]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase
  作者：Ping Lan、F. Anthony Romero、Dariusz Wodka、Andrew J. Kassick、Qun Dang、Tony Gibson、Daniel Cashion、Gaochao Zhou、Yuli Chen、Xiaoping Zhang、Aihua Zhang、Ying Li、Maria E. Trujillo、Qing Shao、Margaret Wu、Shiyao Xu、Huaibing He、Deidre MacKenna、Jocelyn Staunton、Kevin T. Chapman、Ann Weber、Iyassu K. Sebhat、Gergely M. Makara

  DOI：10.1021/acs.jmedchem.7b01344

  日期：2017.11.9

  AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.