Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I).
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.
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.
Xiaoke
X
Guo
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Xianglei
X
Ma
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Qian
Q
Yang
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Jing
J
Xu
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Lu
L
Huang
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.
Jianmin
J
Jia
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Jiaojiao
J
Shan
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Li
L
Liu
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.
Weilin
W
Chen
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.
Hongxi
H
Chu
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.
Jinlian
J
Wei
Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Xiaojin
X
Zhang
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.
Haopeng
H
Sun
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tyq@cpu.edu.cn.
Yiqun
Y
Tang
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.
Qidong
Q
You
D061605:Administration, Intravenous; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D010879:Piperazines
Atrial fibrillation; Kv1.5 potassium channel; Structure–activity relationship