isopropyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)pyrrolidine-1-carboxylate

• 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: isopropyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)pyrrolidine-1-carboxylate
• 英文别名: Propan-2-yl 3-[1-(4-methylsulfonylphenyl)-2-oxopyridin-4-yl]oxypyrrolidine-1-carboxylate；propan-2-yl 3-[1-(4-methylsulfonylphenyl)-2-oxopyridin-4-yl]oxypyrrolidine-1-carboxylate
• 化学式: C₂₀H₂₄N₂O₆S
• 分子量: 420.486
• InChiKey: DVWVHROLZABXOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-苄氧基-2(1H)-吡啶酮 在 盐酸 、 copper(l) iodide 、 8-羟基喹啉 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 20.0~145.0 ℃ 、101.33 kPa 条件下， 反应 5.5h， 生成 isopropyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Discovery of 5-Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119

  摘要：

  G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic beta-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.

  DOI：

  10.1021/jm501175v

文献信息

• Discovery of 5-Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1<i>H</i>)-one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119
  作者：Dean A. Wacker、Ying Wang、Matthias Broekema、Karen Rossi、Steven O’Connor、Zhenqiu Hong、Ginger Wu、Sarah E. Malmstrom、Chen-Pin Hung、Linda LaMarre、Anjaneya Chimalakonda、Lisa Zhang、Li Xin、Hong Cai、Cuixia Chu、Stephanie Boehm、Jacob Zalaznick、Randolph Ponticiello、Larisa Sereda、Song-Ping Han、Rachel Zebo、Bradley Zinker、Chiuwa Emily Luk、Richard Wong、Gerry Everlof、Yi-Xin Li、Chunyu K. Wu、Michelle Lee、Steven Griffen、Keith J. Miller、John Krupinski、Jeffrey A. Robl

  DOI：10.1021/jm501175v

  日期：2014.9.25

  G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic beta-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.