The α2/3-selective GABAkine KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization. The metabolic study of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. A deuterated analog of KRM-II-81, D5-KRM-II-81 was constructed by targeting these sites of metabolism that could be evaluated as a potentially longer-acting analog. The PK study of both compounds revealed higher brain disposition of KRM-II-81 than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the t<sub>max</sub> for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally despite its lack of augmented exposure. These findings of this new orally active anticonvulsant GABAkine, D5-KRM-II-81 will be presented.

Synthesis, metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81

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ACS Fall 2022

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