Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors.
Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations.
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
Qian
Q
Yang
Jing
J
Xu
Li
L
Zhang
Hongxi
H
Chu
Peng
P
Yu
Yingying
Y
Zhu
Jinglian
J
Wei
Weilin
W
Chen
Yaozhong
Y
Zhang
Xiaojin
X
Zhang
Haopeng
H
Sun
Yiqun
Y
Tang
Qidong
Q
You
D000818:Animals; D015195:Drug Design; D057809:HEK293 Cells; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D006835:Hydrazones; D007211:Indoles; D051666:Kv1.5 Potassium Channel; C000588458:N-(4-chlorophenyl)-2-(5-methoxy-3-((2-tosylhydrazono)methyl)-1H-indol-1-yl)acetamide; D026902:Potassium Channel Blockers; C030374:indole
Atrial fibrillation (AF); Indole derivatives; Kv1.5; Structure–activity relationship (SAR)