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

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.

• Authors: 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
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 81 Pg. 89-94 (Jun 23 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24824064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• KCNA5 protein, human
• Kv1.5 Potassium Channel
• Piperazines

Topics

• 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, chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship