2-methyl-5-trifluoromethyloxazole-4-carboxylic acid {6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}amide | 1279083-86-1

• 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-methyl-5-trifluoromethyloxazole-4-carboxylic acid {6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}amide
• 英文别名: 2-Methyl-5-trifluoromethyloxazole-4-carboxylic Acid{6-[(2-Methoxyethyl)methylamino]pyridin-3-yl}amide；N-[6-[2-methoxyethyl(methyl)amino]pyridin-3-yl]-2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxamide
• CAS: 1279083-86-1
• 化学式: C₁₅H₁₇F₃N₄O₃
• 分子量: 358.32
• InChiKey: MONQMZFWAUSONS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  80.5
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  N-(2-methoxyethyl)-N-methyl-5-nitropyridin-2-amine 在 5% Pd(II)/C(eggshell) 、 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 2-methyl-5-trifluoromethyloxazole-4-carboxylic acid {6-[(2-methoxyethyl)(methyl)amino]pyridin-3-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

• 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
  作者：Yimin Qian、Stanley J. Wertheimer、Mushtaq Ahmad、Adrian Wai-Hing Cheung、Fariborz Firooznia、Matthew M. Hamilton、Stuart Hayden、Shiming Li、Nicholas Marcopulos、Lee McDermott、Jenny Tan、Weiya Yun、Liang Guo、Anjula Pamidimukkala、Yingsi Chen、Kuo-Sen Huang、Gwendolyn B. Ramsey、Toni Whittard、Karin Conde-Knape、Rebecca Taub、Cristina M. Rondinone、Jefferson Tilley、David Bolin

  DOI：10.1021/jm101580m

  日期：2011.4.14

  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).