Initial SAR exploration was focused on the aromatic tail region of compound 12. Both rational design by medicinal chemists and computational enumeration by Schrödinger's AutoDesigner algorithm were applied to generate a diverse set of design ideas. The large number of designs were filtered by molecular properties, a CNS MPO, a druglikeness MPO and synthetic tractability, etc. The top scoring designs were progressed into FEP+ calculations to predict hDAO inhibitory potency. The compounds with favorable predicted hDAO potency were selected for synthesis at Charles River Laboratories (CRL). Additionally, active compounds were tested in the MDCK-MDR1 assays to assess cell permeability and efflux ratio (ER).