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Medicinal Chemistry
ISSN (Print): 1573-4064
ISSN (Online): 1875-6638
VOLUME: 10
ISSUE: 5
DOI: 10.2174/1573406409666131128144755      Price:  $58









Discovery of Aroyl Piperazine Derivatives as IKr & IKs Dual Inhibitors for Cardiac Arrhythmia Treatment

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Author(s): Xiaoke Guo, Haopeng Sun, Lvpei Du, Lu Huang, Jing Xu, Yingying Zhu, Peng Yu, Xiaojin Zhang, Yiqun Tang and Qidong You
Pages 497-505 (9)
Abstract:
Combined blockade of IKr and IKs 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 (IKr) and hKCNQ1/KCNE1 (IKs) potassium channels, and half of them exhibited improved dual IKr and IKs 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.
Graphical Abstract:
Keywords:
IKr and IKs dual inhibitor, arrhythmia, class III antiarrhythmic agents.
Affiliation:
China Pharmaceutical University, 24 Tongjia Road, Nanjing, China.