Design and synthesis of non-peptide peptidomimetic inhibitors of the aspartic peptidases

Novel drug discovery methods have been developed targeting aspartic peptidase conformational ensembles. A series of 3,4-disubstitued piperidines were designed via a structure-generating program as aspartic peptidase inhibitors and synthesized both in solution and on solid phase. An azepine scaffold was also designed and synthesized as a potential aspartic peptidase inhibitor.; The piperidines were rationally designed based on structural information previously obtained with peptide-based inhibitors and shown to stabilize a preexisting, previously unobserved enzyme conformer. New methods for targeting conformational ensembles including Domino Conformation Transitions and Merged Group Binding (MGB) Searches have been subsequently developed.; An efficient, enantioselective synthesis was developed to access the piperidines via an asymmetric dihydroxylation/reduction protocol. Solid phase organic syntheses via a traceless triazene linker afforded the piperidine potential inhibitors in high yields and purities. The piperidines were shown to be selective inhibitors of porcine and R. chinensis pepsin. Further biological evaluation led to a new porcine pepsin assay, bioanalytical characterization of porcine pepsin, enzyme affinity chromatography, solubility assays, and new piperidine analogs.; A 3-hydroxy-4-aryl azepine scaffold was designed as an aspartic peptidase inhibitor. An enantioselective synthesis was developed to afford the cyclic scaffold via a double mesylate displacement reaction. The azepine inhibitors were shown to be micromolar inhibitors of porcine pepsin sufficient as lead compounds.; In summary a multidisciplinary approach to drug design utilizing the tools of computational chemistry, synthetic organic chemistry, solid phase organic synthesis, medicinal chemistry, and enzymology have been utilized in the design, synthesis and evaluation of novel aspartic peptidase inhibitors.