Epilepsy is one of the most commonly occurring neurological conditions and the ultimate cause of neurological disability. It affects 1-2 % of total the population and among those patients, about 33% suffer with refractory epilepsy. HZ-166 is an anticonvulsant, anxiolytic, and anti-hyperalgesic agent, and a GABAA alpha2/alpha3 receptor subtype-selective ligand with no sedation nor ataxia. However, the ester function in HZ-166 might undergo metabolism into the corresponding carboxylic acid, and this would result in poor exposure, high clearance, and low blood brain barrier penetration. The replacement of the ester with heterocycles (oxazole, oxadiazole, and oxazoline) improved metabolic stability and pharmacokinetics, and this led to the clinically progressing non-sedating anticonvulsant KRM-II-81. As back-up compounds, we designed and synthesized novel analogs of KRM-II-81. After docking in the human full-length heteromeric alpha1beta2gammaL GABAA receptor subtype CryroEM structure (6HUO) we tested their biological activity. Importantly, several novel analogs exhibited potent anticonvulsant activity with improved in-vivo and in-vitro stability in the absence of cytotoxicity, sedation, ataxia, and loss of righting response.

- Epilepsy is one of the most commonly occurring neurological conditions and the ultimate cause of neurological disability. It affects 1-2 % of total the population and among those patients, about 33% suffer with refractory epilepsy. HZ-166 is an anticonvulsant, anxiolytic, and anti-hyperalgesic agent, and a GABA~A~ alpha2/alpha3 receptor subtype-selective ligand with no sedation nor ataxia. However, the ester function in HZ-166 might undergo metabolism into the corresponding carboxylic acid, and this would result in poor exposure, high clearance, and low blood brain barrier penetration. The replacement of the ester with heterocycles (oxazole, oxadiazole, and oxazoline) improved metabolic stability and pharmacokinetics, and this led to the clinically progressing non-sedating anticonvulsant KRM-II-81. As back-up compounds, we designed and synthesized novel analogs of KRM-II-81. After docking in the human full-length heteromeric alpha1beta2gammaL GABA~A~ receptor subtype CryroEM structure (6HUO) we tested their biological activity. Importantly, several novel analogs exhibited potent anticonvulsant activity with improved _in-vivo_ and _in-vitro_ stability in the absence of cytotoxicity, sedation, ataxia, and loss of righting response.

Design, synthesis, and characterization of novel analogs of clinically progressing gamma-aminobutyric acid type A (GABA<sub>A</sub>) receptor α2/α3 subtype-selective ligand KRM-II-81 for treatment of epilepsy

ACS Spring 2022

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Design, synthesis, and characterization of novel analogs of clinically progressing gamma-aminobutyric acid type A (GABAA) receptor α2/α3 subtype-selective ligand KRM-II-81 for treatment of epilepsy

Design, synthesis, and characterization of novel analogs of clinically progressing gamma-aminobutyric acid type A (GABA_A) receptor α2/α3 subtype-selective ligand KRM-II-81 for treatment of epilepsy