New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4<i>H</i>-benzo[<i>f</i>]imidazo[1,5-<i>a</i>][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

ABSTRACT: KRM-II-81 (1) is an imidazodiazepine GABA_A receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a K_i of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than suf

SUBMITTER: Sharmin D 

PROVIDER: S-EPMC12931607 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature