2-chloro-4-cyclopropylthiazole-5-carboxylic acid | 1503893-73-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 2-chloro-4-cyclopropylthiazole-5-carboxylic acid
• 英文别名: 2-Chloro-4-cyclopropyl-1,3-thiazole-5-carboxylic acid；2-chloro-4-cyclopropyl-1,3-thiazole-5-carboxylic acid
• CAS: 1503893-73-9
• 化学式: C₇H₆ClNO₂S
• 分子量: 203.649
• InChiKey: AKBPHGIHLZVELY-UHFFFAOYSA-N

物化性质

• 沸点：
  372.9±44.0 °C(Predicted)
• 密度：
  1.634±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  78.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-chloro-4-cyclopropylthiazole-5-carboxylic acid 在 sodium hydride 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 二氯甲烷 、 mineral oil 为溶剂， 反应 74.17h， 生成 4-cyclopropyl-N-(trans-5-hydroxy-2-adamantyl)-2-[(1S)-2-methoxy-1-methylethoxy]thiazole-5-carboxamide
  参考文献：
  名称：

  Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

  摘要：

  11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11 beta-HSD1 activity alleviates metabolic syndrome.

  DOI：

  10.1021/jm4016729
• 作为产物：
  描述：

  ethyl 2-chloro-4-cyclopropylthiazole-5-carboxylate 在 potassium trimethylsilonate 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以100%的产率得到2-chloro-4-cyclopropylthiazole-5-carboxylic acid
  参考文献：
  名称：

  Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

  摘要：

  11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11 beta-HSD1 activity alleviates metabolic syndrome.

  DOI：

  10.1021/jm4016729

文献信息

• Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice
  作者：Frederick W. Goldberg、Alexander G. Dossetter、James S. Scott、Graeme R. Robb、Scott Boyd、Sam D. Groombridge、Paul D. Kemmitt、Tove Sjögren、Pablo Morentin Gutierrez、Joanne deSchoolmeester、John G. Swales、Andrew V. Turnbull、Martin J. Wild

  DOI：10.1021/jm4016729

  日期：2014.2.13

  11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11 beta-HSD1 activity alleviates metabolic syndrome.