Potential Anxiolytic Agents. Part 4: Novel Orally-Active N5-Substituted Pyrido[1,2-a]benzimidazoles with High GABA-A Receptor Affinity

A series of pyrido[1,2-a]benzimidazoles (PBIs) with substitution on the N5-nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24, which has an IC50 of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.