Epilepsy affects 1-2% of the global population and around 33% of those patients suffer from refractory epilepsy. It is also a generally occurring neurological condition and one of the causes of neurological disability.  Epilepsy affects 1-2% of the global population and around 33% of those patients suffer from refractory epilepsy. It is also a generally occurring neurological condition and one of the causes of neurological disability. A GABAA α2/α3 receptor subtype-selective ligand, HZ-166 is an anti-hyperalgesic, anxiolytic, and anticonvulsant compound without any adverse effects. However, high clearance, poor exposure, and low blood-brain barrier penetration resulted because of the possible metabolism of ester function into corresponding the acid. Later, the metabolic stability and pharmacokinetics were improved by replacing the ester function of HZ-166 with heterocycles including oxazoles, and oxadiazoles. This resulted in clinically progressing lead compound KRM-II-81, which is a non-sedating and anticonvulsant compound. For the backup of KRM-II-81, we designed and synthesized many novel analogs. Also, the biological activities of these compounds were tested after their molecular docking in the human full-length heteromeric α1β3γ2L GABAA receptor subtype CryroEM structure (6HUO). Remarkably, several novel analogs showed potent anticonvulsant activities in various seizure models in mice and rats. Moreover, in-vivo and in-vitro metabolic stability were improved and no adverse effects including ataxia, sedation, loss of righting response, and cytotoxicity were seen as desired. This work will be presented.

Synthesis of analogs of KRM-II-81, gamma aminobutyric acid type A (GABAA) receptor α2/α3 subtype-selective ligand, for epilepsy treatment without any adverse effects

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ACS Fall 2022

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