AbstractSmall-molecule inhibitors of the zinc metalloprotease insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), are a promising new class of potential cognitive enhancers for the treatment of neurodegenerative disorders such as Alzheimer’s disease. Previous studies identified a series of sulfonamide-substituted benzylhydroxamic acids with fair BBB permeability, no indication of efflux and subnanomolar potency. We herein report our further structural optimization of this compound series focusing on various alterations to the sulfonamide group. Notably, introduction of dihydropyridopyrimidine provided the most active small-molecule inhibitor compound reported to date, with an IC50 value of 34 nM. Molecular modeling studies, based on free energy perturbation simulations, show that the accommodation of the explored substituents on the binding mode proposed explain the experimental SAR herein reported and provide a rationale for the enhanced affinity of the optimized compounds.