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Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors |
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| Authors: | Xiaoke Guo Qian Yang Jing Xu Li Zhang Hongxi Chu Peng Yu Yingying Zhu Jinglian Wei Weilin Chen Yaozhong Zhang Xiaojin Zhang Haopeng Sun Yiqun Tang Qidong You |
| Affiliation: | 1. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;3. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;4. Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China |
| Abstract: | 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. |
| Keywords: | Atrial fibrillation (AF) Kv1.5 Indole derivatives Structure–activity relationship (SAR) |
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