Our group's research has previously led to potent bicycle-based POP inhibitors, revealing that the introduction of bicyclic scaffolds can enhance the metabolic stability of these inhibitors. In the shift toward POP-FAP dual inhibitors, we then aimed to improve these bicyclic scaffolds while simultaneously constraining the known inhibitor Cbz-Pro-Prolinal 1 and failed drug candidate Talabostat. Our results indicate that we were not only able to obtain potent compounds using our computationally guided optimizations of known inhibitors, but that we were able to use this method along with synthetic developments to produce an inhibitor with comparable potency to a drug that reached Phase III clinical trials. Currently, we are carrying out cell-based assays to assess the activity of our leads in cellulo, as well as performing further experiments to optimize the activity and pharmacokinetic properties of our leads including 10a, 10c, and 12a as selective POP inhibitors and 10f and 12c as dual inhibitors.