ethyl 4-ethoxy-2-methyl-thiazole-5-carboxylate | 1547490-39-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 4-ethoxy-2-methyl-thiazole-5-carboxylate
• 英文别名: Ethyl4-ethoxy-2-methylthiazole-5-carboxylate；ethyl 4-ethoxy-2-methyl-1,3-thiazole-5-carboxylate
• CAS: 1547490-39-0
• 化学式: C₉H₁₃NO₃S
• 分子量: 215.273
• InChiKey: VJFQUCBANHLRHO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  76.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 4-ethoxy-2-methyl-thiazole-5-carboxylate 在 水 、 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 、 potassium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 4-ethoxy-N-(trans-5-hydroxy-2-adamantyl)-2-methyl-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：

  溴代丙二酸二乙酯 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 2.0h， 生成 ethyl 4-ethoxy-2-methyl-thiazole-5-carboxylate
  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

• [EN] 5-MEMBERED AND BICYCLIC HETEROCYCLIC AMIDES AS INHIBITORS OF ROCK<br/>[FR] AMIDES HÉTÉROCYCLIQUES À 5 CHAÎNONS ET BICYCLIQUES UTILISÉS EN TANT QU'INHIBITEURS DE ROCK
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2019014308A1

  公开（公告）日：2019-01-17

  The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically-acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

  本发明提供了化合物的结构式（I）：或其立体异构体、互变异构体或药学上可接受的盐，其中所有变量如本文所定义。这些化合物是选择性ROCK抑制剂。本发明还涉及包含这些化合物的药物组合物以及使用它们治疗心血管、平滑肌、肿瘤学、神经病理学、自身免疫、纤维化和/或炎症性疾病的方法。
• 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.