2,6-dinonyl-1-methylpyridinium trifluoromethanesulfonate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磺酸及其衍生物
• 英文名称: 2,6-dinonyl-1-methylpyridinium trifluoromethanesulfonate
• 英文别名: 1-Methyl-2,6-di(nonyl)pyridin-1-ium;trifluoromethanesulfonate；1-methyl-2,6-di(nonyl)pyridin-1-ium;trifluoromethanesulfonate
• 化学式: CF₃O₃S*C₂₄H₄₄N
• 分子量: 495.69
• InChiKey: HWLIXBXTJGJDEH-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  7.15
• 重原子数：
  33
• 可旋转键数：
  16
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  69.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-壬炔 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 生成 2,6-dinonyl-1-methylpyridinium trifluoromethanesulfonate
  参考文献：
  名称：

  Structure–Affinity Relationships (SARs) and Structure–Kinetics Relationships (SKRs) of K_v11.1 Blockers

  摘要：

  K(v)11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent proarrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of K(v)11.1 blockers next to their structure affinity relationships. We learned that despite dramatic differences in affinities and association rates, there were hardly any variations in the dissociation rate constants of these molecules with residence times (RTs) of a few minutes only. Hence, we synthesized 16 novel molecules, in particular in the pyridinium class of compounds, to further address this peculiar phenomenon. We found molecules with very short RTs (e.g., 0.34 min for 37) and much longer RTs (e.g., 105 min for 38). This enabled us to construct a k(on)-k(off)-K-D kinetic map for all compounds and subsequently divide the map into four provisional quadrants, providing a possible framework for a further and more precise categorization of K(v)11.1 blockers. Additionally, two representative compounds (21 and 38) were tested in patch clamp assays, and their RTs were linked to their functional IC50 values. Our findings strongly suggest the importance of the simultaneous study of ligand affinities and kinetic parameters, which may help to explain and predict K(v)11.1-mediated cardiotoxicity.

  DOI：

  10.1021/acs.jmedchem.5b00518

文献信息

• Structure–Affinity Relationships (SARs) and Structure–Kinetics Relationships (SKRs) of K_v11.1 Blockers
  作者：Zhiyi Yu、Jacobus P. D. van Veldhoven、Julien Louvel、Ingrid M. E. ’t Hart、Martin B. Rook、Marcel A. G. van der Heyden、Laura H. Heitman、Adriaan P. IJzerman

  DOI：10.1021/acs.jmedchem.5b00518

  日期：2015.8.13

  K(v)11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent proarrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of K(v)11.1 blockers next to their structure affinity relationships. We learned that despite dramatic differences in affinities and association rates, there were hardly any variations in the dissociation rate constants of these molecules with residence times (RTs) of a few minutes only. Hence, we synthesized 16 novel molecules, in particular in the pyridinium class of compounds, to further address this peculiar phenomenon. We found molecules with very short RTs (e.g., 0.34 min for 37) and much longer RTs (e.g., 105 min for 38). This enabled us to construct a k(on)-k(off)-K-D kinetic map for all compounds and subsequently divide the map into four provisional quadrants, providing a possible framework for a further and more precise categorization of K(v)11.1 blockers. Additionally, two representative compounds (21 and 38) were tested in patch clamp assays, and their RTs were linked to their functional IC50 values. Our findings strongly suggest the importance of the simultaneous study of ligand affinities and kinetic parameters, which may help to explain and predict K(v)11.1-mediated cardiotoxicity.