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

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.
Xiaoke Guo 1,  Xianglei Ma 2,  Qian Yang 3,  Jing Xu 2,  Lu Huang 2,  Jianmin Jia 4,  Jiaojiao Shan 2,  Li Liu 5,  Weilin Chen 1,  Hongxi Chu 1,  Jinlian Wei 1,  Xiaojin Zhang 6,  Haopeng Sun 7,  Yiqun Tang 8,  Qidong You 9
Affiliations

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.

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