Exploring Simple Drug Scaffolds from the Generated Database Chemical Space Reveals a Chiral Bicyclic Azepane with Potent Neuropharmacology

To assess how much structural diversity remains unexploited in simple drug scaffolds, we investigated ring systems functionalized with amine handles. Starting from the ring systems database GDB-4c, we enumerated 1139 possible amines and diamines with up to two five-, six-, or seven-membered rings. From the 680 cases not listed in PubChem, we synthesized several unprecedented <i>cis</i>- and <i>trans</i>-fused azepanes and tested possible targets predicted using the polypharmacology browser PPB2. From this screening campaign, an <i>N</i>-benzylated azepane emerged as a potent inhibitor of monoamine transporters with some selectivity toward norepinephrine (NET, SLC6A2) and dopamine transporter (DAT, SLC6A3) inhibition (IC₅₀ < 100 nM) in combination with σ-1R inhibition (IC₅₀ ≈ 110 nM). The <i>in vitro</i> profile, favorable pharmacokinetic properties, and preliminary behavioral and metabolomic effects in mice suggest a potential of <i>N</i>-benzylated bicyclic azepanes to target neuropsychiatric disorders. These experiments highlight the potential of simple but still unexplored scaffolds for drug discovery.