N-(1H-imidazol-2-yl)-2-chloro-4-fluoro-5-(isobutyramidomethyl)benzamide | 1381846-11-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(1H-imidazol-2-yl)-2-chloro-4-fluoro-5-(isobutyramidomethyl)benzamide
• 英文别名: 2-chloro-4-fluoro-N-(1H-imidazol-2-yl)-5-[(2-methylpropanoylamino)methyl]benzamide
• CAS: 1381846-11-2
• 化学式: C₁₅H₁₆ClFN₄O₂
• 分子量: 338.769
• InChiKey: BRDXAWQPAQGSDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  86.9
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-chloro-5-(isobutyramidomethyl)-4-fluorobenzoic acid 、 2-氨基咪唑硫酸盐 在 N,N-二异丙基乙胺 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以30%的产率得到N-(1H-imidazol-2-yl)-2-chloro-4-fluoro-5-(isobutyramidomethyl)benzamide
  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-2-Benzamide Compounds Useful for the Treatment of Osteoarthritis
  申请人：Kuklish Steven Lee

  公开号：US20120157506A1

  公开（公告）日：2012-06-21

  The present invention provides compounds of the formula below or pharmaceutical salts thereof, wherein R1, R2 and R3 are as described herein; methods of treating osteoarthritis using the compounds; and a process for preparing the compounds.

  本发明提供了下面公式的化合物或其药用盐，其中R1、R2和R3如本文所述；使用这些化合物治疗骨关节炎的方法；以及制备这些化合物的方法。
• US8252831B2
  申请人：——

  公开号：US8252831B2

  公开（公告）日：2012-08-28
• Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors
  作者：Matthew A. Schiffler、Stephen Antonysamy、Shobha N. Bhattachar、Kristina M. Campanale、Srinivasan Chandrasekhar、Bradley Condon、Prashant V. Desai、Matthew J. Fisher、Christopher Groshong、Anita Harvey、Michael J. Hickey、Norman E. Hughes、Scott A. Jones、Euibong J. Kim、Steven L. Kuklish、John G. Luz、Bryan H. Norman、Richard E. Rathmell、John R. Rizzo、Thomas W. Seng、Stefan J. Thibodeaux、Timothy A. Woods、Jeremy S. York、Xiao-Peng Yu

  DOI：10.1021/acs.jmedchem.5b01249

  日期：2016.1.14

  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.