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Article Abstract
Epilepsy is one of the most common and life-threatening neurological diseases, and the GABARs are important therapeutic targets for epilepsy. Herein, a series of novel 2,7-disubstituted isoindolin-1-one derivatives were designed and synthesized, and extensive structure-activity relationships led to a number of highly potent PAMs of GABARs with EC values at 10-10 M level and value of 5-15-fold. In particular, exhibited strong in vitro potentiation effects toward both synaptic and extra-synaptic GABARs, and produced highly potent in vivo efficacies in mouse seizure models, including sc-PTZ (ED = 8.20 mg/kg), MES (ED = 2.68 mg/kg), and pilocarpine-induced SE model. Furthermore, displayed a high selectivity for GABARs over other key CNS ion channels (>100-fold). It also possessed desirable plasma PK properties and BBB penetration ability. Altogether, could serve as a unique lead compound for further developing new antiseizure agents with differentiated pharmacological profiles.
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