Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I)

Xiaoke Guo; Xianglei Ma; Qian Yang; Jing Xu; Lu Huang; Jianmin Jia; Jiaojiao Shan; Li Liu; Weilin Chen; Hongxi Chu; Jinlian Wei; Xiaojin Zhang; Haopeng Sun; Yiqun Tang; Qidong You

doi:10.1016/j.ejmech.2014.03.075

Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I)

Eur J Med Chem. 2014 Jun 23:81:89-94. doi: 10.1016/j.ejmech.2014.03.075. Epub 2014 Mar 28.

Authors

Xiaoke Guo¹, Xianglei Ma², Qian Yang³, Jing Xu², Lu Huang², Jianmin Jia⁴, Jiaojiao Shan², Li Liu⁵, Weilin Chen¹, Hongxi Chu¹, Jinlian Wei¹, Xiaojin Zhang⁶, Haopeng Sun⁷, Yiqun Tang⁸, Qidong You⁹

Affiliations

¹ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
² Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁴ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁵ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
⁶ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
⁷ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: sunhaopeng@163.com.
⁸ Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tyq@cpu.edu.cn.
⁹ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.

PMID: 24824064
DOI: 10.1016/j.ejmech.2014.03.075

Abstract

Kv1.5 potassium channel is an efficacious and safe therapeutic target for the treatment of atrial fibrillation (AF), the most common arrhythmia that threatens human. Herein, by modifying the hit compound 7k from an in-house database, 48 derivatives were synthesized for the assay of their Kv1.5 inhibitory effects by whole cell patch clamp technique. Six compounds which showed better potency than the positive compound dronedarone were selected for the next evaluation of their drug-like properties. Compound 8 exhibited balanced solubility and permeability. It also showed acceptable pharmacodynamics profile with very low acute toxicity. Taking all these data into account, compound 8 can serve as a promising lead for the development of novel therapeutic agent for the treatment of AF.

Keywords: Atrial fibrillation; Kv1.5 potassium channel; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intravenous
Animals
Atrial Fibrillation / drug therapy*
Dose-Response Relationship, Drug
Drug Discovery*
HEK293 Cells
Humans
Kv1.5 Potassium Channel / antagonists & inhibitors*
Mice
Molecular Structure
Piperazines / administration & dosage
Piperazines / chemistry
Piperazines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

KCNA5 protein, human
Kv1.5 Potassium Channel
Piperazines