N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide | 588939-85-9

• 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: N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide
• 英文别名: N-(5-chloro-1,3-thiazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonylphenyl)propanamide
• CAS: 588939-85-9
• 化学式: C₁₈H₂₁ClN₂O₃S₂
• 分子量: 412.961
• InChiKey: AWVVMUPZAROUQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  26
• 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：
  113
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-氯-2-氨基噻唑 、 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid 在 草酰氯 、 N,N-二甲基甲酰胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 四氢呋喃 为溶剂， 反应 17.67h， 生成 N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide
  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

• Heteroaromatic glucokinase activators
  申请人：Bizzaro Thomas Fred

  公开号：US20050261503A1

  公开（公告）日：2005-11-24

  2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 3-position being a substituted phenyl group and at the 2-position being a methyl cycloalkyl 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，其中在3位上的取代基为取代苯基，2位上的取代基为甲基环烷基环，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。
• US6610846B1
  申请人：——

  公开号：US6610846B1

  公开（公告）日：2003-08-26
• US6951945B2
  申请人：——

  公开号：US6951945B2

  公开（公告）日：2005-10-04
• US7223868B2
  申请人：——

  公开号：US7223868B2

  公开（公告）日：2007-05-29
• Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients
  作者：Ramakanth Sarabu、Fred T. Bizzarro、Wendy L. Corbett、Mark T. Dvorozniak、Wanping Geng、Joseph F. Grippo、Nancy-Ellen Haynes、Stanley Hutchings、Lisa Garofalo、Kevin R. Guertin、Darryl W. Hilliard、Marek Kabat、Robert F. Kester、Wang Ka、Zhenmin Liang、Paige E. Mahaney、Linda Marcus、Franz M. Matschinsky、David Moore、Jagdish Racha、Roumen Radinov、Yi Ren、Lida Qi、Michael Pignatello、Cheryl L. Spence、Thomas Steele、John Tengi、Joseph Grimsby

  DOI：10.1021/jm3008689

  日期：2012.8.23

  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.