Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 21, Pages 6466-6476Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.08.041
Keywords
Atrial fibrillation (AF); Kv1.5; Indole derivatives; Structure-activity relationship (SAR)
Funding
- State Key Laboratory of Natural Medicines
- Jiang Su Key Laboratory of Drug Design and Optimization
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2012ZX09103101-002, 012ZX09401-005]
- innovation Program for the Postgraduates in Jiangsu
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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. (C) 2013 Elsevier Ltd. All rights reserved.
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