4-cyclobutyl-2-(methylthio)pyrimidine-5-carboxylic acid | 1191095-45-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-cyclobutyl-2-(methylthio)pyrimidine-5-carboxylic acid
• 英文别名: 4-cyclobutyl-2-methylsulfanylpyrimidine-5-carboxylic acid
• CAS: 1191095-45-0
• 化学式: C₁₀H₁₂N₂O₂S
• 分子量: 224.283
• InChiKey: RRSQJDJATJXDII-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  88.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-cyclobutyl-2-(methylthio)pyrimidine-5-carboxylic acid 在 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.0h， 生成 4-cyclobutyl-2-[(1,1-dioxothian-4-yl)amino]-N-(5-hydroxy-2-adamantyl)pyrimidine-5-carboxamide
  参考文献：
  名称：

  Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors

  摘要：

  11 beta-Hydroxysteroid dehydrogenase 1 (11 beta-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11 beta-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.

  DOI：

  10.1021/jm3013163
• 作为产物：
  描述：

  methyl 2-(cyclobutanecarbonyl)-3-(dimethylamino)acrylate 在 lithium hydroxide monohydrate 、 sodium acetate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 4-cyclobutyl-2-(methylthio)pyrimidine-5-carboxylic acid
  参考文献：
  名称：

  Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors

  摘要：

  11 beta-Hydroxysteroid dehydrogenase 1 (11 beta-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11 beta-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.

  DOI：

  10.1021/jm3013163

文献信息

• Adamantyl Iminocarbonyl-Substituted Pyrimidines As Inhibitors Of 11-Beta-HSD1 826
  申请人：Bennett Stuart Norman Lile

  公开号：US20110092526A1

  公开（公告）日：2011-04-21

  A compound of formula (I): and pharmaceutically-acceptable salts thereof, wherein the variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are also described herein.

  公式(I)的化合物：以及药理可接受的盐，其中变量组在内部定义；它们用于抑制11βHSD1，制造它们的过程以及包含它们的药物组合物也在本文中描述。
• SUBSTITUTED PYRIMIDIN-5-CARBOXAMIDES 281
  申请人：GILL Adrian Liam

  公开号：US20090264401A1

  公开（公告）日：2009-10-22

  A compound of formula (I): and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are also described.

  一种具有化学式（I）的化合物： 及其药用盐，其中变量基团在其中定义；还描述了它们在抑制11βHSD1中的应用，制备它们的方法以及包含它们的药物组合物。
• [EN] SUBSTITUTED PYRIMIDIN-5-CARBOXAMIDES 281<br/>[FR] PYRIMIDINE-5-CARBOXAMIDES SUBSTITUÉS
  申请人：ASTRAZENECA AB

  公开号：WO2009130496A1

  公开（公告）日：2009-10-29

  A compound of formula (I) and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are also described.
• Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors
  作者：Frederick W. Goldberg、Andrew G. Leach、James S. Scott、Wendy L. Snelson、Sam D. Groombridge、Craig S. Donald、Stuart N. L. Bennett、Cristian Bodin、Pablo Morentin Gutierrez、Amy C. Gyte

  DOI：10.1021/jm3013163

  日期：2012.12.13

  11 beta-Hydroxysteroid dehydrogenase 1 (11 beta-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11 beta-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.