N-[(5-cyclopentyl-1,2-oxazol-3-yl)methyl]adamantan-1-amine

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-[(5-cyclopentyl-1,2-oxazol-3-yl)methyl]adamantan-1-amine
• 化学式: C₁₉H₂₈N₂O
• 分子量: 300.444
• InChiKey: BTODPXUKMBPODR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  38.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  环戊基乙酮 在 sodium tetrahydroborate 、 四溴化碳 、 盐酸羟胺 、 potassium tert-butylate 、 三乙胺 、 三苯基膦 、 cesium iodide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 异丙醇 、 甲苯 为溶剂， 反应 10.0h， 生成 N-[(5-cyclopentyl-1,2-oxazol-3-yl)methyl]adamantan-1-amine
  参考文献：
  名称：

  In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

  摘要：

  Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound 10b, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties. The antiviral efficacy of compound 10b was also synergistic with oseltamivir carboxylate. Interestingly, binding kinetic studies (K-d, K-on, and K-off) revealed several AM2-S31N inhibitors that have similar K-d values but significantly different K-on and K-off values. Overall, this study identified a potent lead compound (10b) with improved in vitro PK properties that is suitable for the in vivo mouse model studies.

  DOI：

  10.1021/acs.jmedchem.7b01536

文献信息

• In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses
  作者：Yuanxiang Wang、Yanmei Hu、Shuting Xu、Yongtao Zhang、Rami Musharrafieh、Raymond Kin Hau、Chunlong Ma、Jun Wang

  DOI：10.1021/acs.jmedchem.7b01536

  日期：2018.2.8

  Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound 10b, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties. The antiviral efficacy of compound 10b was also synergistic with oseltamivir carboxylate. Interestingly, binding kinetic studies (K-d, K-on, and K-off) revealed several AM2-S31N inhibitors that have similar K-d values but significantly different K-on and K-off values. Overall, this study identified a potent lead compound (10b) with improved in vitro PK properties that is suitable for the in vivo mouse model studies.