1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-2-(2-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)-4-methyl-pentan-2-ol | 1348815-11-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-2-(2-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)-4-methyl-pentan-2-ol
• 英文别名: 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-[(2-propan-2-yl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methyl]pentan-2-ol
• CAS: 1348815-11-1
• 化学式: C₂₃H₂₇F₄N₃O
• 分子量: 437.48
• InChiKey: GODBXMQWXMDZOL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  61.8
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,2,2-trifluoro-N-{4-[6-(5-fluoro-2-methylphenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-2-isopropyl-pyrimidin-5-yl}acetamide 在 四甲基胍 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.75h， 以33%的产率得到1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-2-(2-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)-4-methyl-pentan-2-ol
  参考文献：
  名称：

  Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects

  摘要：

  Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.

  DOI：

  10.1021/jm4019178

文献信息

• Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
  申请人：Bekkali Younes

  公开号：US20050176706A1

  公开（公告）日：2005-08-11

  Compounds of Formula (IA), (IB), (IC), and (ID) wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as respectively defined herein for Formula (IA), (IB), (IC), and (ID), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

  化合物的公式为（IA），（IB），（IC）和（ID），其中R1，R2，R3，R4，R5和R6分别定义为公式（IA），（IB），（IC）和（ID）中所述，或其互变异构体，前药，溶剂化物或盐; 包含这些化合物的药物组合物以及使用这些化合物调节糖皮质激素受体功能的方法和治疗由糖皮质激素受体功能介导或以炎症，过敏或增生过程为特征的疾病状态或病情的方法。
• US8741897B2
  申请人：——

  公开号：US8741897B2

  公开（公告）日：2014-06-03
• Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects
  作者：Christian Harcken、Doris Riether、Daniel Kuzmich、Pingrong Liu、Raj Betageri、Mark Ralph、Michel Emmanuel、Jonathan T. Reeves、Angela Berry、Donald Souza、Richard M. Nelson、Alison Kukulka、Tazmeen N. Fadra、Ljiljana Zuvela-Jelaska、Roger Dinallo、Jörg Bentzien、Gerald H. Nabozny、David S. Thomson

  DOI：10.1021/jm4019178

  日期：2014.2.27

  Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.