sodium;(E,3R,5S)-7-[4-(4-fluorophenyl)-2-[(2-methyl-1,2,4-triazol-3-yl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate | 1026024-79-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: sodium;(E,3R,5S)-7-[4-(4-fluorophenyl)-2-[(2-methyl-1,2,4-triazol-3-yl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate
• CAS: 1026024-79-2
• 化学式: C₂₃H₂₆FN₆O₄*Na
• 分子量: 492.485
• InChiKey: SAQMLBVLCXGFSF-GMXCBYEPSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -1.45
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  149
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  C₃₀H₃₉FN₆O₄ 在 盐酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 sodium;(E,3R,5S)-7-[4-(4-fluorophenyl)-2-[(2-methyl-1,2,4-triazol-3-yl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate
  参考文献：
  名称：

  (3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential

  摘要：

  3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950), Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

  DOI：

  10.1021/jm800001n

文献信息

• (3<i>R,</i>5<i>S,E</i>)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1<i>H</i>-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential
  作者：Saleem Ahmad、Cort S. Madsen、Philip D. Stein、Evan Janovitz、Christine Huang、Khehyong Ngu、Sharon Bisaha、Lawrence J. Kennedy、Bang-Chi Chen、Rulin Zhao、Doree Sitkoff、Hossain Monshizadegan、Xiaohong Yin、Carol S. Ryan、Rongan Zhang、Mary Giancarli、Eileen Bird、Ming Chang、Xing Chen、Robert Setters、Debra Search、Shaobin Zhuang、Van Nguyen-Tran、Carolyn A. Cuff、Thomas Harrity、Celia J. Darienzo、Tong Li、Richard A. Reeves、Michael A. Blanar、Joel C. Barrish、Robert Zahler、Jeffrey A. Robl

  DOI：10.1021/jm800001n

  日期：2008.5.1

  3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950), Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.