(S)-2-cyclopentyl-N-(quinolin-6-ylmethyl)but-3-yn-2-amine | 1160741-94-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (S)-2-cyclopentyl-N-(quinolin-6-ylmethyl)but-3-yn-2-amine
• 英文别名: (2S)-2-cyclopentyl-N-(quinolin-6-ylmethyl)but-3-yn-2-amine
• CAS: 1160741-94-5
• 化学式: C₁₉H₂₂N₂
• 分子量: 278.397
• InChiKey: JRMPNFALGGAFRC-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  24.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  、 (S)-2-cyclopentyl-N-(quinolin-6-ylmethyl)but-3-yn-2-amine 在 copper(II) sulfate 、 sodium ascorbate 作用下， 以 水 、 叔丁醇 为溶剂， 以67%的产率得到3-(4-((S)-1-cyclopentyl-1-(quinolin-6-ylmethylamino)ethyl)-1H-1,2,3-triazol-1-yl)-1-(2,3,5,6-tetrafluorophenoxy)heptan-2-one
  参考文献：
  名称：

  Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

  摘要：

  A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.

  DOI：

  10.1021/jm901633v
• 作为产物：
  描述：

  在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以0.041 g的产率得到(S)-2-cyclopentyl-N-(quinolin-6-ylmethyl)but-3-yn-2-amine
  参考文献：
  名称：

  Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

  摘要：

  A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.

  DOI：

  10.1021/jm901633v

文献信息

• Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy
  作者：Katrien Brak、Iain D. Kerr、Kimberly T. Barrett、Nobuhiro Fuchi、Moumita Debnath、Kenny Ang、Juan C. Engel、James H. McKerrow、Patricia S. Doyle、Linda S. Brinen、Jonathan A. Ellman

  DOI：10.1021/jm901633v

  日期：2010.2.25

  A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.
• Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease
  作者：R. Jeffrey Neitz、Clifford Bryant、Steven Chen、Jiri Gut、Estefania Hugo Caselli、Servando Ponce、Somenath Chowdhury、Haichao Xu、Michelle R. Arkin、Jonathan A. Ellman、Adam R. Renslo

  DOI：10.1016/j.bmcl.2015.06.066

  日期：2015.11

  Inhibition of the cysteine protease cruzain from Trypanosoma cruzi has been studied pre-clinically as a new chemotherapeutic approach to treat Chagas' disease. Efficacious effects of vinylsulfone-based cruzain inhibitors in animal models support this therapeutic hypothesis. More recently, substrate-activity screening was used to identify nonpeptidic tetrafluorophenoxymethyl ketone inhibitors of cruzain that showed promising efficacy in animal models. Herein we report efforts to further optimize the in vitro potency and in vivo pharmacokinetic properties of this new class of cruzain inhibitors. Through modifications of the P1, P2 and/or P3 positions, new analogs have been identified with reduced lipophilicity, enhanced potency, and improved oral exposure and bioavailability. (C) 2015 Elsevier Ltd. All rights reserved.