2-(6-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

• 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: 2-(6-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
• 英文别名: 2-[6-[[4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid；2-[6-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid
• 化学式: C₂₂H₁₈F₃NO₄S
• 分子量: 449.45
• InChiKey: YBBZJHLFUPKHJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  96.9
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-(三氟甲基)硫代苯甲酰胺 在 sodium tetrahydroborate 、 potassium carbonate 、 potassium iodide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 乙腈 为溶剂， 反应 26.0h， 生成 2-(6-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
  参考文献：
  名称：

  Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents

  摘要：

  The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor delta (PPAR delta) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPAR delta agonists would increase insulin secretion and sensibility by FFA1 and PPAR delta activation. In this study, we hybrid FFA1 agonist AM-4668 with PPAR delta agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPAR delta. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPAR delta agonist could be a valuable therapy for type 2 diabetes. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.12.069

文献信息

• Design, synthesis and Structure–activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
  作者：Zheng Li、Qianqian Qiu、Xue Xu、Xuekun Wang、Lei Jiao、Xin Su、Miaobo Pan、Wenlong Huang、Hai Qian

  DOI：10.1016/j.ejmech.2016.02.040

  日期：2016.5

  The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of

  游离脂肪酸受体1（FFA1 / GPR40）作为治疗2型糖尿病的新靶标已引起人们的关注。相对较高的分子量和亲脂性阻碍了包括FAK1激动剂在内的数个系列的FFA1激动剂（由于对肝毒性的担忧而在III期研究中终止的最先进的化合物）。为了通过降低亲脂性来开发具有低肝毒性风险的有效FFA1激动剂，TAK-875的中间苯基被11个极性五元杂芳族化合物所取代。随后，对SAR的系统探索和分子建模的应用导致了化合物44的鉴定，它是一种出色的FFA1激动剂，在正常和2型糖尿病小鼠中均具有强大的降血糖作用，即使在两倍摩尔的TAK-875剂量下也具有低血糖风险和肝毒性。同时，指出了两个重要发现。首先，我们的噻唑系列中的甲基占据了一个小的疏水亚口袋，与TAK-875没有相互作用。此外，激动活性显示与噻唑核心和末端苯环之间的二面角具有良好的相关性。这些结果促进了对配体结合口袋的了解，并可能有助于设计更有希望的FFA1激动剂。
• Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents
  作者：Zheng Li、Yueming Chen、Zongtao Zhou、Liming Deng、Yawen Xu、Lijun Hu、Bing Liu、Luyong Zhang

  DOI：10.1016/j.ejmech.2018.12.069

  日期：2019.2

  The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor delta (PPAR delta) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPAR delta agonists would increase insulin secretion and sensibility by FFA1 and PPAR delta activation. In this study, we hybrid FFA1 agonist AM-4668 with PPAR delta agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPAR delta. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPAR delta agonist could be a valuable therapy for type 2 diabetes. (C) 2018 Elsevier Masson SAS. All rights reserved.