2-(difluoromethyl)-5-(propionamidomethyl)-N-(4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)nicotinamide | 1415089-61-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(difluoromethyl)-5-(propionamidomethyl)-N-(4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)nicotinamide
• 英文别名: 2-(difluoromethyl)-N-[4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-5-[(propanoylamino)methyl]pyridine-3-carboxamide；2-(difluoromethyl)-N-[5-methyl-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-5-[(propanoylamino)methyl]pyridine-3-carboxamide
• CAS: 1415089-61-0
• 化学式: C₂₂H₂₀F₅N₅O₂
• 分子量: 481.425
• InChiKey: TZFQDPLANIAZLL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  99.8
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-溴-1-(4-(三氟甲基)苯基)-1-丙酮 在 盐酸 、 羟胺 、 碳酸氢钠 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 88.0h， 生成 2-(difluoromethyl)-5-(propionamidomethyl)-N-(4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)nicotinamide
  参考文献：
  名称：

  Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors

  摘要：

  As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 mu M. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8 center dot H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

  DOI：

  10.1021/acs.jmedchem.5b01249

文献信息

• Novel Imidazole Derivatives Useful for the Treatment of Arthritis
  申请人：Hughes Norman Earle

  公开号：US20120302608A1

  公开（公告）日：2012-11-29

  The present invention provides compounds of the formula below: where A, X and R1-R6 are as described herein, a pharmaceutical salt thereof, and a pharmaceutical composition containing this compound; methods of treating pain associated with osteoarthritis using one of the compounds or a pharmaceutically acceptable salt thereof, and processes for preparing the compounds.

  本发明提供了以下式的化合物： 其中A、X和R1-R6如本文所述，其药用盐，以及含有该化合物的药物组合物；使用其中一种化合物或其药用盐治疗与骨关节炎相关的疼痛的方法，以及制备这些化合物的方法。
• US8648200B2
  申请人：——

  公开号：US8648200B2

  公开（公告）日：2014-02-11
• [EN] NOVEL IMIDAZOLE DERIVATIVES USEFUL FOR THE TREATMENT OF ARTHRITIS<br/>[FR] NOUVEAUX DÉRIVÉS D'IMIDAZOLE UTILES POUR LE TRAITEMENT DE L'ARTHRITE
  申请人：LILLY CO ELI

  公开号：WO2012161965A1

  公开（公告）日：2012-11-29

  The present invention provides compounds of the formula below: where A, X and R1-R6 are as described herein, a pharmaceutical salt thereof, and a pharmaceutical composition containing this compound; methods of treating pain associated with osteoarthritis using one of the compounds or a pharmaceutically acceptable salt thereof, and processes for preparing the compounds.