2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-(2,4'-bipyridin-5-yl)amide) | 1085841-79-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-(2,4'-bipyridin-5-yl)amide)
• 英文别名: 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-5-yl)-amide；2-phenyl-N-(6-piperidin-4-ylpyridin-3-yl)-5-(trifluoromethyl)-1,3-oxazole-4-carboxamide
• CAS: 1085841-79-7
• 化学式: C₂₁H₁₉F₃N₄O₂
• 分子量: 416.403
• InChiKey: FXSKGRWGTAVDPJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  80
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-(2,4'-bipyridin-5-yl)amide) 、 环丙甲酸 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以77.6%的产率得到2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (1'-cyclopropanecarbonyl-1',2',3',4',5',6'-hexahydro[2,4']bipyridinyl-5-yl)amide
  参考文献：
  名称：

  Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity and Diabetes

  摘要：

  Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxarnides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 mu M) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, PO, qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).

  DOI：

  10.1021/jm101580m
• 作为产物：
  描述：

  2-溴-5-硝基吡啶 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0~100.0 ℃ 、344.75 kPa 条件下， 反应 4.67h， 生成 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (1',2',3',4',5',6'-hexahydro-(2,4'-bipyridin-5-yl)amide)
  参考文献：
  名称：

  Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity and Diabetes

  摘要：

  Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxarnides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 mu M) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, PO, qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).

  DOI：

  10.1021/jm101580m

文献信息

• Diacylglycerol Acyltransferase Inhibitors
  申请人：Bolin David Robert

  公开号：US20090093497A1

  公开（公告）日：2009-04-09

  Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

  本文提供的是公式(I)的化合物，以及其药物可接受的盐，其中取代基如规范中所述。这些化合物和含有它们的药物组合物对于治疗疾病，例如肥胖症、2型糖尿病和代谢综合征是有用的。
• Diacylglycerol acyltransferase inhibitors
  申请人：VIA Pharmaceuticals, Inc.

  公开号：US08058299B2

  公开（公告）日：2011-11-15

  Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

  本文提供的化合物具有以下公式（I）：以及其药学上可接受的盐，其中取代基如规范中所述。这些化合物及含有它们的药物组合物可用于治疗疾病，例如肥胖症、2型糖尿病和代谢综合征。
• US8058299B2
  申请人：——

  公开号：US8058299B2

  公开（公告）日：2011-11-15
• US8115011B2
  申请人：——

  公开号：US8115011B2

  公开（公告）日：2012-02-14
• US8153644B2
  申请人：——

  公开号：US8153644B2

  公开（公告）日：2012-04-10