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

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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 cis- and trans-fused azepanes and tested possible targets predicted using the polypharmacology browser PPB2. From this screening campaign, an N-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 in vitro profile, favorable pharmacokinetic properties, and preliminary behavioral and metabolomic effects in mice suggest a potential of N-benzylated bicyclic azepanes to target neuropsychiatric disorders. These experiments highlight the potential of simple but still unexplored scaffolds for drug discovery.