2-amino-4-{2-[5-bis(ethoxycarbonyloxymethyl)phosphono]furanyl}-5-isobutylthiazole

• 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-amino-4-{2-[5-bis(ethoxycarbonyloxymethyl)phosphono]furanyl}-5-isobutylthiazole
• 英文别名: 2-Amino-5-isobutyl-4-{-2-[5-bis(ethoxycarbonyloxymethyl)phosphono]-furanyl}thiazole；[[5-[2-Amino-5-(2-methylpropyl)-1,3-thiazol-4-yl]furan-2-yl]-(ethoxycarbonyloxymethoxy)phosphoryl]oxymethyl ethyl carbonate
• 化学式: C₁₉H₂₇N₂O₁₀PS
• 分子量: 506.471
• InChiKey: AZQUIYMANSTZFM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  33
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  187
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  2-氨基-5-异丁基-4-[5-膦酰基-2-呋喃基]噻唑 、 ethyl iodomethyl carbonate 在 tertiary alkyl amine 作用下， 反应 24.0h， 生成 2-amino-4-{2-[5-bis(ethoxycarbonyloxymethyl)phosphono]furanyl}-5-isobutylthiazole
  参考文献：
  名称：

  Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase

  摘要：

  Oral delivery of previously disclosed purine and benzimidazole fructose-1,6 bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular wright (> 600) Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was Implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%) Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM

  DOI：

  10.1021/jm101035x

文献信息

• Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase
  作者：Qun Dang、Yan Liu、Daniel K. Cashion、Srinivas Rao Kasibhatla、Tao Jiang、Frank Taplin、Jason D. Jacintho、Haiqing Li、Zhili Sun、Yi Fan、Jay DaRe、Feng Tian、Wenyu Li、Tony Gibson、Robert Lemus、Paul D. van Poelje、Scott C. Potter、Mark D. Erion

  DOI：10.1021/jm101035x

  日期：2011.1.13

  Oral delivery of previously disclosed purine and benzimidazole fructose-1,6 bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular wright (> 600) Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was Implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%) Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM