We compared de novo generated molecules with optimized potency for the A 2A R to those with optimized potency and maximized or minimized CL, VDSS or FU. Subsequently, the scaled PK and affinity parameter estimates for the generated compounds were used in a previously published mice QSP model to compare the tumor inhibition efficacy of the predicted inhibitors. We found different PK optimization scenarios strongly influenced which molecules and scaffolds were preferentially generated. Moreover, the trends in the physicochemical properties of the generated molecules corresponded well with the relative difference between molecules in the PK dataset.