3-nitro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzoic acid methyl ester | 1227244-08-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-nitro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzoic acid methyl ester
• 英文别名: 3-nitro-4-[N-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid methyl ester；Methyl 3-nitro-4-[(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)amino]benzoate；methyl 3-nitro-4-[(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)amino]benzoate
• CAS: 1227244-08-7
• 化学式: C₂₃H₂₈N₂O₄
• 分子量: 396.486
• InChiKey: GUYDNQUQPNTXIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  84.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-nitro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzoic acid methyl ester 在 palladium on activated charcoal 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 4.0h， 生成 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester
  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 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 硫酸 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 甲苯 为溶剂， 生成 3-nitro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzoic acid methyl ester
  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

• RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists
  作者：Hiroki Kakuta、Nobumasa Yakushiji、Ryosuke Shinozaki、Fuminori Ohsawa、Shoya Yamada、Yui Ohta、Kohei Kawata、Mariko Nakayama、Manabu Hagaya、Chisa Fujiwara、Makoto Makishima、Shigeyuki Uno、Akihiro Tai、Ami Maehara、Masaru Nakayama、Toshitaka Oohashi、Hiroyuki Yasui、Yutaka Yoshikawa

  DOI：10.1021/ml300055n

  日期：2012.5.10

  Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.
• 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.