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

• Published in: European journal of medicinal chemistry 2011-03, Vol.46 (3), p.934-943
• Main Authors: Qi, Jinlong, Zhang, Fan, Mi, Yi, Fu, Yan, Xu, Wen, Zhang, Diqun, Wu, Yibing, Du, Xiaona, Jia, Qingzhong, Wang, Kewei, Zhang, Hailin
• Format: Article
• Language: English
• Subjects: Animals; Arrhythmias, Cardiac - drug therapy; Atomic absorption Rb+ efflux assay; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Drug Design; Epilepsy - drug therapy; Humans; KCNQ Potassium Channels - metabolism; KCNQ2/3 channel activator; Kv7/KCNQ/M-channel; Medical sciences; Miscellaneous; Patch-Clamp Techniques; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazolo[1,5-a]pyrimidin-7(4H)-ones; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rubidium - metabolism; Structure-Activity Relationship; Whole-cell patch-clamp recording
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.010

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. A new series of pyrazolo[1,5-a]pyrimidin-7(4H)-ones (I) were synthesized and demonstrated for their activity as opener of KCNQ2/Q3 potassium channel. The most active analog compound 17 opened KCNQ2/Q3 potassium channel with an EC50 of 0.06 μM. [Display omitted] ► A series of novel pyrazolo [1,5-a] pyrimidin-7(4H)-ones (PPOs) were synthesized. ► A few lead compounds as M channel openers were identified. ► Structure-activity relationships of PPOs as M channel openers were established. ► Derivatives of PPOs were identified as the novel Kv7/KCNQ channel openers.