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 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.