Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators

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• 作者：Jinlong Qi ; Fan Zhang ; Yi Mi ; Yan Fu ; Wen Xu ; Diqun Zhang ; Yibing Wu ; Xiaona Du ; Qingzhong Jia ; Kewei Wang ; Hailin Zhang
• 关键词：Pyrazolo[1 ; 5-a]pyrimidin-7(4H)-ones ; Kv7/KCNQ/M-channel ; KCNQ2/3 channel activator ; Atomic absorption Rb⁺ efflux assay ; Whole-cell patch-clamp recording
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 2011
• 年：2011
• 卷：46
• 期：3
• 页码：934-943
• 全文大小：1593 K

文摘

Voltage-gated Kv7/KCNQ/M-potassium channels play a pivotal role in controlling neuronal excitability. Genetic reduction of KCNQ channel activity as a result of mutations causes various human diseases such as epilepsy and arrhythmia. Therefore, discovery of small molecules that activate KCNQ channels is an important strategy for clinical intervention of membrane excitability related disorders. In this study, a series of pyrazolo[1,5-a]pyrimidin-7(4H)-ones (PPOs) have been found to be novel activators (openers) of KCNQ2/3 potassium channels through high-throughput screening by using atomic absorption rubidium efflux assay. Based on structure–activity relationship (SAR), the substituted PPOs have been optimized. The 5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (17) was identified as a novel, potent, and selective KCNQ2/3 potassium channel opener by patch-clamp recording assay.