2-bromo-5-(pivalamidomethyl)benzoic acid | 1381846-27-0

• 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: 2-bromo-5-(pivalamidomethyl)benzoic acid
• 英文别名: 2-bromo-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid；2-Bromo-5-(pivalamidomethyl)benzoic acid
• CAS: 1381846-27-0
• 化学式: C₁₃H₁₆BrNO₃
• 分子量: 314.179
• InChiKey: KIMZYDVYCVVENK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-bromo-5-(pivalamidomethyl)benzoic 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19%的产率得到N-(1H-imidazol-2-yl)-2-bromo-5-(pivalamidomethyl)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
• 作为产物：
  描述：

  N-hydroxymethyl trimethylacetamide 、 2-溴苯甲酸 在 硫酸 作用下， 以19%的产率得到2-bromo-5-(pivalamidomethyl)benzoic acid
  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

• Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof
  申请人：Shanghai Hengrui Pharmaceutical Co., Ltd.

  公开号：US10081629B2

  公开（公告）日：2018-09-25

  Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof are provided. Specifically, amide derivatives represented by general formula (I) are provided. The amide derivatives represented by general formula (I) can be used as a therapeutic agent, particularly as an inhibitor for microsomal prostaglandin E synthase-1 (mPGES-1), and also to treat and/or prevent diseases or illnesses such as inflammation and/or pain etc. The definition of each substituent group in general formula (I) is the same as the definition in the description.

  本发明提供了酰胺衍生物及其药学上可接受的盐、制备方法和药物应用。具体而言，本发明提供了通式（I）代表的酰胺衍生物。通式（I）代表的酰胺衍生物可用作治疗剂，特别是作为微粒体前列腺素 E 合酶-1（mPGES-1）的抑制剂，还可用于治疗和/或预防炎症和/或疼痛等疾病。通式（I）中各取代基的定义与说明中的定义相同。
• [EN] AMIDE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREFOR AND MEDICINAL APPLICATION THEREOF<br/>[FR] DÉRIVÉS D'AMIDES ET LEURS SELS PHARMACEUTIQUEMENT ACCEPTABLES, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION MÉDICALE<br/>[ZH] 酰胺类衍生物及其可药用盐、其制备方法及其在医药上的应用
  申请人：SHANGHAI HENGRUI PHARM CO LTD

  公开号：WO2015158204A1

  公开（公告）日：2015-10-22

  本发明涉及酰胺类衍生物及其可药用盐、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式（I）所示酰胺类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为治疗剂，特别是作为微粒体前列腺素E合成酶-1（mPGES-1）抑制剂的用途和其在制备治疗和/或预防炎症和/或疼痛等疾病或病症的药物中的用途，其中通式（I）中的各取代基的定义与说明书中的定义相同。
• AMIDE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREFOR AND MEDICINAL APPLICATION THEREOF
  申请人：Shanghai Hengrui Pharmaceutical Co. Ltd.

  公开号：EP3133068B1

  公开（公告）日：2020-11-25
• AMIDE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREOF AND MEDICINAL APPLICATION THEREOF
  申请人：Shanghai Hengrui Pharmaceutical Co., Ltd.

  公开号：US20170037044A1

  公开（公告）日：2017-02-09

  Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof are provided. Specifically, amide derivatives represented by general formula (I) are provided. The amide derivatives represented by general formula (I) can be used as a therapeutic agent, particularly as an inhibitor for microsomal prostaglandin E synthase-1 (mPGES-1), and also to treat and/or prevent diseases or illnesses such as inflammation and/or pain etc. The definition of each substituent group in general formula (I) is the same as the definition in the description.
• 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.