2-oxo-1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid | 1227244-48-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: 2-oxo-1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid
• 英文别名: methyl 2-oxo-1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)-3H-benzimidazole-5-carboxylate
• CAS: 1227244-48-5
• 化学式: C₂₄H₂₈N₂O₃
• 分子量: 392.498
• InChiKey: VUASEOFBOXJRNV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-oxo-1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid 在 sodium hydroxide 、 盐酸 作用下， 以 甲醇 、 四氢呋喃 、 水 为溶剂， 反应 0.5h， 以45 mg的产率得到2-oxo-1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)-3H-benzimidazole-5-carboxylic acid
  参考文献：
  名称：

  Mechanism of Retinoid X Receptor Partial Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic Acid and Structural Development To Increase Potency

  摘要：

  We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar E-max (67 +/- 2%) and lower EC50 (15 +/- 0 nM) compared to those of 4a (E-max = 75 +/- 4%, EC50 = 143 +/- 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the a-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

  DOI：

  10.1021/jm400033f
• 作为产物：
  描述：

  4-碘-3-硝基苯甲酸甲酯 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 palladium on activated charcoal 、 氢气 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 作用下， 以 乙酸乙酯 、 1,2-二氯乙烷 、 甲苯 为溶剂， 生成 2-oxo-1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid
  参考文献：
  名称：

  Mechanism of Retinoid X Receptor Partial Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic Acid and Structural Development To Increase Potency

  摘要：

  We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar E-max (67 +/- 2%) and lower EC50 (15 +/- 0 nM) compared to those of 4a (E-max = 75 +/- 4%, EC50 = 143 +/- 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the a-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

  DOI：

  10.1021/jm400033f

文献信息

• Mechanism of Retinoid X Receptor Partial Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1<i>H</i>-benzotriazole-5-carboxylic Acid and Structural Development To Increase Potency
  作者：Fuminori Ohsawa、Shoya Yamada、Nobumasa Yakushiji、Ryosuke Shinozaki、Mariko Nakayama、Kohei Kawata、Manabu Hagaya、Toshiki Kobayashi、Kazutaka Kohara、Yuuki Furusawa、Chisa Fujiwara、Yui Ohta、Makoto Makishima、Hirotaka Naitou、Akihiro Tai、Yutaka Yoshikawa、Hiroyuki Yasui、Hiroki Kakuta

  DOI：10.1021/jm400033f

  日期：2013.3.14

  We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar E-max (67 +/- 2%) and lower EC50 (15 +/- 0 nM) compared to those of 4a (E-max = 75 +/- 4%, EC50 = 143 +/- 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the a-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.