Discovery of Aroyl Piperazine Derivatives as I_Kr & I_Ks Dual Inhibitors for Cardiac Arrhythmia Treatment

Title:Discovery of Aroyl Piperazine Derivatives as I_Kr & I_Ks Dual Inhibitors for Cardiac Arrhythmia Treatment

Volume: 10 Issue: 5

Author(s): Xiaoke Guo, Haopeng Sun, Lvpei Du, Lu Huang, Jing Xu, Yingying Zhu, Peng Yu, Xiaojin Zhang, Yiqun Tang and Qidong You

Affiliation:

Keywords: I_Kr and I_Ks dual inhibitor, arrhythmia, class III antiarrhythmic agents.

Abstract: Combined blockade of I_Kr and I_Ks potassium channels is considered to be a promising therapeutic strategy for arrhythmia. In this study, we designed and synthesized 15 derivatives through modifying the hit compound 7 that was discovered by screening in-house database by whole-patch clamp technique. All of the compounds were evaluated on CHO and HEK 293 cell lines stably expressing hERG (I_Kr) and hKCNQ1/KCNE1 (I_Ks) potassium channels, and half of them exhibited improved dual I_Kr and I_Ks inhibitory effects compared to the hit compound. Compounds 7a and 7b with potent dual inhibitory activities were selected for further in vivo evaluations. Due to the preferable pharmacological behaviors, compound 7a deserved further optimization as a promising lead compound.

Cite this article as:

Guo Xiaoke, Sun Haopeng, Du Lvpei, Huang Lu, Xu Jing, Zhu Yingying, Yu Peng, Zhang Xiaojin, Tang Yiqun and You Qidong, Discovery of Aroyl Piperazine Derivatives as I_Kr & I_Ks Dual Inhibitors for Cardiac Arrhythmia Treatment, Medicinal Chemistry 2014; 10 (5) . https://dx.doi.org/10.2174/1573406409666131128144755