(S)-2-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)isonicotinic acid | 1354694-78-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (S)-2-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)isonicotinic acid
• 英文别名: 2-[[(2S)-3-cyclopentyl-2-[4-(trifluoromethyl)imidazol-1-yl]propanoyl]amino]pyridine-4-carboxylic acid
• CAS: 1354694-78-2
• 化学式: C₁₈H₁₉F₃N₄O₃
• 分子量: 396.369
• InChiKey: FZILUFZIMSAEFV-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  97.1
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (R)-methyl 3-cyclopentyl-2-hydroxypropanoate 在 吡啶 、 2,6-二甲基吡啶 、 盐酸 、 草酰氯 、 N,N-二甲基甲酰胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 37.08h， 生成 (S)-2-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)isonicotinic acid
  参考文献：
  名称：

  Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus

  摘要：

  Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic beta-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

  DOI：

  10.1021/jm2014887

文献信息

• Discovery of (<i>S</i>)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1<i>H</i>-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus
  作者：Jeffrey A. Pfefferkorn、Angel Guzman-Perez、John Litchfield、Robert Aiello、Judith L. Treadway、John Pettersen、Martha L. Minich、Kevin J. Filipski、Christopher S. Jones、Meihua Tu、Gary Aspnes、Hud Risley、Jianwei Bian、Benjamin D. Stevens、Patricia Bourassa、Theresa D’Aquila、Levenia Baker、Nicole Barucci、Alan S. Robertson、Francis Bourbonais、David R. Derksen、Margit MacDougall、Over Cabrera、Jing Chen、Amanda Lee Lapworth、James A. Landro、William J. Zavadoski、Karen Atkinson、Nahor Haddish-Berhane、Beijing Tan、Lili Yao、Rachel E. Kosa、Manthena V. Varma、Bo Feng、David B. Duignan、Ayman El-Kattan、Sharad Murdande、Shenping Liu、Mark Ammirati、John Knafels、Paul DaSilva-Jardine、Laurel Sweet、Spiros Liras、Timothy P. Rolph

  DOI：10.1021/jm2014887

  日期：2012.2.9

  Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic beta-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.