(2R)-2-[3-chloro-4-(methylsulfanyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonan-7-yl]-N-[(2R,4R)-4-hydroxy-4-phenylbutan-2-yl]-N-methylpropanamide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (2R)-2-[3-chloro-4-(methylsulfanyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonan-7-yl]-N-[(2R,4R)-4-hydroxy-4-phenylbutan-2-yl]-N-methylpropanamide
• 英文别名: 2(R)-(3-chloro-4-methylsulfanylphenyl)-3-(2(R),3(R)-diphenyl-1,4-dioxaspiro[4.4]non-7(R)-yl)-N-(2(R)-hydroxy-1(R)-methyl-2-phenylethyl)-N-methylpropionamide；(2R)-2-(3-chloro-4-methylsulfanylphenyl)-3-[(2R,3R,8R)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonan-8-yl]-N-[(1R,2R)-1-hydroxy-1-phenylpropan-2-yl]-N-methylpropanamide
• 化学式: C₃₉H₄₂ClNO₄S
• 分子量: 656.286
• InChiKey: ZTEQPNBACYTBQY-FLXCMTTJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  46
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  84.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R)-2-[3-chloro-4-(methylsulfanyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonan-7-yl]-N-[(2R,4R)-4-hydroxy-4-phenylbutan-2-yl]-N-methylpropanamide 在 草酰氯 、 硫酸 、 二甲基二环氧乙烷 、 N,N-二甲基甲酰胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 丙酮 、 甲苯 为溶剂， 反应 38.0h， 生成 Piragliatin
  参考文献：
  名称：

  Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients

  摘要：

  Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase beta-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

  DOI：

  10.1021/jm3008689
• 作为产物：
  描述：

  3-氯-4-甲硫基苯乙酸 在 正丁基锂 、 三甲基乙酰氯 、 potassium carbonate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 丙酮 为溶剂， 反应 3.83h， 生成 (2R)-2-[3-chloro-4-(methylsulfanyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonan-7-yl]-N-[(2R,4R)-4-hydroxy-4-phenylbutan-2-yl]-N-methylpropanamide
  参考文献：
  名称：

  Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients

  摘要：

  Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase beta-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

  DOI：

  10.1021/jm3008689

文献信息

• Substituted-cycloalkyl and oxygenated-cycloalkyl glucokinase activators
  申请人：——

  公开号：US20030225283A1

  公开（公告）日：2003-12-04

  2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 2-position being a substituted phenyl group and at the 3-position being a polar ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes.

  2,3-二取代N-杂环丙酰胺，其中2-位置的取代物是取代苯基，3-位置的取代物是极性环，这些丙酰胺是葡萄糖激酶激活剂，可增加胰岛素分泌，用于治疗2型糖尿病。
• [EN] SUBSTITUTED PHENYLACETAMIDES AND THEIR USE AS GLUCOKINASE ACTIVATORS<br/>[FR] ACTIVATEURS DE GLUCOKINASE OXYGENES CYCLOALKYLE OU SUBSTITUES CYCLOALKYLE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2003095438A1

  公开（公告）日：2003-11-20

  Compounds of the formula (I); wherein formula (II) represents a substituted group, an oxa-cycloalkyl group or a thia-cycloalkyl group, are glucokinase activators useful in the treatment of type II diabetes.

  式(I)的化合物；其中式(II)代表取代基团，氧杂环烷基团或硫杂环烷基团，是一种在治疗II型糖尿病中有用的葡萄糖激酶激活剂。
• SUBSTITUTED PHENYLACETAMIDES AND THEIR USE AS GLUCOKINASE ACTIVATORS
  申请人：F. Hoffmann-La Roche AG

  公开号：EP1501815A1

  公开（公告）日：2005-02-02
• US7105671B2
  申请人：——

  公开号：US7105671B2

  公开（公告）日：2006-09-12
• US7259166B2
  申请人：——

  公开号：US7259166B2

  公开（公告）日：2007-08-21