2-(4-Fluorophenyl)-1H-benzo[d]imidazole as a Promising Template for the Development of Metabolically Robust, alpha 1 beta 2 gamma 2GABA-A Receptor-Positive Allosteric Modulators

Modulation of alpha 1 beta 2 gamma 2GABA-A receptor subpopu-lation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the alpha 1/gamma 2 interface of the GABA-A receptor is limited to imidazo[1,2-a]pyridine derivatives that undergo rapid biotransformation. In response to a deficiency in the chemical repertoire of GABA-A receptors, we identified a series of 2-(4-fluorophenyl)-1H-benzo-[d]imidazoles as positive allosteric modulators (PAMs) with improved metabolic stabi l i t y and reduced potential for hepatotox-icity, where lead molecules 9 and 23 displayed interesting features in a prelimi n a r y investigation. We further disclose that the identified scaffold shows a preference for interaction with the alpha 1/gamma 2 interface of the GABA-A receptor, delivering several PAMs of the GABA-A receptor. The present work provides usef u l chemical templates to further explore the therapeutic potential of GABA-A receptor ligands and enriches the chemical space of molecules suitable for the interaction with the alpha 1/gamma 2 interface.