Design and synthesis of novel non-peptide inhibitors of aspartic proteases

The design and synthesis of novel non-peptide peptidomimetic inhibitors targeting porcine pepsin is described. The design of these inhibitors utilized computer modeling and computer-aided drug design methodologies to target two separate conformers of the enzyme ensemble. The three classes of inhibitors synthesized were cyclic sulfonamides, carbocyclic diols and diazepines.; Cyclic sulfonamide inhibitors were modeled in order to incorporate functionality that would increase their aqueous solubility. This goal was achieved by incorporating a morpholine subunit into the synthesis of these inhibitors. The compound was successfully synthesized and biological evaluation against porcine pepsin demonstrated a much lower inhibition than their hydrophobic counterparts.; Carbocyclic diol inhibitors were designed using a computer-aided ligand generating program. A novel, enantioselective route to these compounds was developed involving an asymmetric dihydroxylation/stereoselective reduction protocol. These compounds were evaluated and shown to have micromolar activity against the target peptidase.; A set of 5,6-disubstituted diazepines were rationally designed utilizing structural information gained from a previously unobserved conformer of renin, an aspartic protease. An efficient synthesis was developed to allow for a wide variety of diversification. Once synthesized, this inhibitor was evaluated against porcine pepsin and was found to have weak inhibition.; In summary, the use of computer-aided design in conjunction with the knowledge of enzyme conformers has presented an interesting challenge in developing novel inhibitors of aspartic proteases.