2-(2-bromo-2,2-difluoroacetylamino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid phenylamide

• 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-(2-bromo-2,2-difluoroacetylamino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid phenylamide
• 英文别名: 2-[(2-bromo-2,2-difluoroacetyl)amino]-N-phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
• 化学式: C₁₈H₁₇BrF₂N₂O₂S
• 分子量: 443.312
• InChiKey: GAZFNWXLZNWENT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  86.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氰基乙酰苯胺 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 ammonium acetate 、 溶剂黄146 、 sodium sulfate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 6.17h， 生成 2-(2-bromo-2,2-difluoroacetylamino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid phenylamide
  参考文献：
  名称：

  Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

  摘要：

  Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of similar to 30 nM, similar to 3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

  DOI：

  10.1021/acs.jmedchem.7b00020

文献信息

• Substituted 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides as inhibitors of calcium-activated chloride channel TMEM16A
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US11358947B2

  公开（公告）日：2022-06-14

  Provided herein are inhibitors of transmembrane protein 16A (TMEM 16A), a Ca2+-activated CI″ channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibitors have potential utility for treatment or management of disorders of epithelial fluid and mucus secretion, hypertension, some cancers, pain, and other diseases.

  本文提供的是跨膜蛋白 16A（TMEM 16A）的抑制剂，TMEM 16A 是一种 Ca2+ 激活的 CI″ 通道，广泛表达于哺乳动物上皮、血管平滑肌、某些肿瘤和电兴奋细胞中。TMEM16A 抑制剂可用于治疗或控制上皮细胞液体和粘液分泌紊乱、高血压、某些癌症、疼痛和其他疾病。
• SUBSTITUTED 2-ACYLAMINO-CYCLOALKYLTHIOPHENE-3-CARBOXYLIC ACID ARYLAMIDES AS INHIBITORS OF CALCIUM-ACTIVATED CHLORIDE CHANNEL TMEM16A
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20200123128A1

  公开（公告）日：2020-04-23

  Provided herein are inhibitors of transmembrane protein 16A (TMEM 16A), a Ca 2+ -activated CI″ channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibitors have potential utility for treatment or management of disorders of epithelial fluid and mucus secretion, hypertension, some cancers, pain, and other diseases.
• Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)
  作者：Eric C. Truong、Puay W. Phuan、Amanda L. Reggi、Loretta Ferrera、Luis J. V. Galietta、Sarah E. Levy、Alannah C. Moises、Onur Cil、Elena Diez-Cecilia、Sujin Lee、Alan S. Verkman、Marc O. Anderson

  DOI：10.1021/acs.jmedchem.7b00020

  日期：2017.6.8

  Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of similar to 30 nM, similar to 3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.