(E)-ethyl 3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)acrylate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (E)-ethyl 3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)acrylate
• 英文别名: ethyl (E)-3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)acrylate；ethyl (E)-3-[2,5-dichloro-4-[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)pyridin-4-yl]oxyphenyl]prop-2-enoate
• 化学式: C₂₈H₂₅Cl₂N₃O₄
• 分子量: 538.43
• InChiKey: MJRLBUNASONRCE-JXMROGBWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  72
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (E)-ethyl 3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)acrylate 在 甲醇 、 sodium tetrahydroborate 、 copper(l) chloride 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以81%的产率得到ethyl 3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)propanoate
  参考文献：
  名称：

  OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

  摘要：

  TGR5激动剂能刺激肠道释放胰高血糖素样肽-1（GLP-1），但全身暴露会引起不必要的副作用，如胆囊充盈。在本研究中，将分子量大、极性强的 DPP-4 抑制剂利拉利汀和之前描述过的 TGR5 激动剂 MN6 联用，生产出一种新型低吸收 TGR5 激动剂 OL3，这种激动剂副作用小，并具有通过激活 TGR5 和抑制 DPP-4 降低血糖的双重功能。在稳定表达人或小鼠 TGR5 和 CRE 驱动荧光素酶基因的 HEK293 细胞中检测 TGR5 的活化情况。根据代底物的水解率评估 DPP-4 抑制作用。在人肠内分泌 NCI-H716 细胞中测量 GLP-1 的分泌。在 Caco-2 细胞中测试了 OL3 的渗透性。在 ICR 和糖尿病 ob/ob 小鼠中评估了 OL3 的急性降糖效果。OL3激活人和小鼠TGR5的EC50分别为86.24和17.36 nmol/L，并刺激人肠内分泌NCI-H716细胞分泌GLP-1（3â30 μ mol/L）。OL3 可抑制人和小鼠 DPP-4，其 IC50 值分别为 18.44 μmol/L 和 69.98 μmol/L 。在 Caco-2 细胞中观察到 OL3 的低渗透性。口服OL3（150毫克/千克）治疗ICR小鼠，1小时后血清中OL3浓度为101.10纳克/毫升，服药后5.5小时降至13.38纳克/毫升，证实OL3在体内的吸收率很低。在ICR小鼠和肥胖/ob小鼠中，口服OL3可显著降低血糖水平，这是激活TGR5刺激肠道分泌GLP-1和抑制DPP-4裂解血浆中GLP-1的协同效应。在ICR小鼠中，口服OL3不会引起胆囊充盈。OL3 是一种低吸收的 TGR5 激动剂，可降低血糖而不会引起胆囊充盈。这项研究为开发治疗 2 型糖尿病的强效 TGR5 激动剂提供了一种新策略，这种激动剂以肠道为靶点，可避免全身副作用。

  DOI：

  10.1038/aps.2016.27
• 作为产物：
  描述：

  4-氯烟酰氯化物 在 草酰氯 、 水 、 palladium diacetate 、 potassium carbonate 、 三乙胺 、 三(邻甲基苯基)磷 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 11.0h， 生成 (E)-ethyl 3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)acrylate
  参考文献：
  名称：

  Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

  摘要：

  Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 angstrom(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

  DOI：

  10.1021/jm500829b

文献信息

• OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition
  作者：Shan-yao Ma、Meng-meng Ning、Qing-an Zou、Ying Feng、Yang-liang Ye、Jian-hua Shen、Ying Leng

  DOI：10.1038/aps.2016.27

  日期：2016.10

  TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. OL3 activated human and mouse TGR5 with an EC50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3–30 μmol/L). OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 μmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects.

  TGR5激动剂能刺激肠道释放胰高血糖素样肽-1（GLP-1），但全身暴露会引起不必要的副作用，如胆囊充盈。在本研究中，将分子量大、极性强的 DPP-4 抑制剂利拉利汀和之前描述过的 TGR5 激动剂 MN6 联用，生产出一种新型低吸收 TGR5 激动剂 OL3，这种激动剂副作用小，并具有通过激活 TGR5 和抑制 DPP-4 降低血糖的双重功能。在稳定表达人或小鼠 TGR5 和 CRE 驱动荧光素酶基因的 HEK293 细胞中检测 TGR5 的活化情况。根据代底物的水解率评估 DPP-4 抑制作用。在人肠内分泌 NCI-H716 细胞中测量 GLP-1 的分泌。在 Caco-2 细胞中测试了 OL3 的渗透性。在 ICR 和糖尿病 ob/ob 小鼠中评估了 OL3 的急性降糖效果。OL3激活人和小鼠TGR5的EC50分别为86.24和17.36 nmol/L，并刺激人肠内分泌NCI-H716细胞分泌GLP-1（3â30 μ mol/L）。OL3 可抑制人和小鼠 DPP-4，其 IC50 值分别为 18.44 μmol/L 和 69.98 μmol/L 。在 Caco-2 细胞中观察到 OL3 的低渗透性。口服OL3（150毫克/千克）治疗ICR小鼠，1小时后血清中OL3浓度为101.10纳克/毫升，服药后5.5小时降至13.38纳克/毫升，证实OL3在体内的吸收率很低。在ICR小鼠和肥胖/ob小鼠中，口服OL3可显著降低血糖水平，这是激活TGR5刺激肠道分泌GLP-1和抑制DPP-4裂解血浆中GLP-1的协同效应。在ICR小鼠中，口服OL3不会引起胆囊充盈。OL3 是一种低吸收的 TGR5 激动剂，可降低血糖而不会引起胆囊充盈。这项研究为开发治疗 2 型糖尿病的强效 TGR5 激动剂提供了一种新策略，这种激动剂以肠道为靶点，可避免全身副作用。
• Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes
  作者：Hongliang Duan、Mengmeng Ning、Qingan Zou、Yangliang Ye、Ying Feng、Lina Zhang、Ying Leng、Jianhua Shen

  DOI：10.1021/jm500829b

  日期：2015.4.23

  Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 angstrom(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.