Discovery of Novel Isoindolin-1-one Derivatives as GABAA Receptors Positive Allosteric Modulators with Antiepileptic Efficacy

Epilepsy is one of the most common and life-threatening neurological diseases, and the GABA_ARs 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 GABA_ARs with EC₅₀ values at 10^-7-10^-8 M level and E_max value of 5-15-fold. In particular, Cpd48 exhibited strong in vitro potentiation effects toward both synaptic and extra-synaptic GABA_ARs, and produced highly potent in vivo efficacies in mouse seizure models, including sc-PTZ (ED₅₀ = 8.20 mg/kg), MES (ED₅₀ = 2.68 mg/kg), and pilocarpine-induced SE model. Furthermore, Cpd48 displayed a high selectivity for GABA_ARs over other key CNS ion channels (>100-fold). It also possessed desirable plasma PK properties and BBB penetration ability. Altogether, Cpd48 could serve as a unique lead compound for further developing new antiseizure agents with differentiated pharmacological profiles.