Shigyo H, Sato S, Shibuya K, Takahashi Y, Yamaguchi T, Sonoki H, Ohta T
Tokyo Research Laboratories, Kowa Co., Ltd., Japan.
Chem Pharm Bull (Tokyo). 1993 Sep;41(9):1573-82. doi: 10.1248/cpb.41.1573.
A series of disubstituted phenylpyridine derivatives was synthesized and their antiarrhythmic effects against chloroform-induced ventricular arrhythmias in mice were examined. Among them, 2- and 3-[2-(3-aminobutyramido)-4-(2,2,2-trifluroethoxy)phenyl]pyri dines (23h, 24h) and 3-[2-(3-aminobutyramido)-4-ethoxyphenyl]pyridine (24i) showed potent antiarrhythmic activity. They had approximately twice the potency of mexiletine (III). Compound 24i was selected from this series as a candidate for further development; it was found to have a class I B electrophysiological character and to show a slow kinetic rate-dependent block (RDB) of the sodium channel in cardiac muscle.
合成了一系列二取代苯基吡啶衍生物，并检测了它们对氯仿诱导的小鼠室性心律失常的抗心律失常作用。其中，2-和3-[2-(3-氨基丁酰胺基)-4-(2,2,2-三氟乙氧基)苯基]吡啶（23h、24h）和3-[2-(3-氨基丁酰胺基)-4-乙氧基苯基]吡啶（24i）表现出强效抗心律失常活性。它们的效力约为美西律（III）的两倍。从该系列中选择化合物24i作为进一步开发的候选物；发现它具有I B类电生理特性，并在心肌中显示出钠通道的慢动力学速率依赖性阻滞（RDB）。
