title: Discovery of aroyl piperazine derivatives as IKr & IKs dual inhibitors for cardiac arrhythmia treatment.
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.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Guo
authors.forename: Haopeng
authors.initials: H
authors.lastname: Sun
authors.forename: Lvpei
authors.initials: L
authors.lastname: Du
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Zhang
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: China Pharmaceutical University, 24 Tongjia Road, Nanjing, China. sunhaopeng@163.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D010042:Ouabain / Q000009:adverse effects; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D010879:Piperazines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D000077489:Piperazine; D010042:Ouabain