Solution and Solid Phase Synthesis of Non-Peptide Peptidomimetic Aspartic Peptidase Inhibitors

Abstract

A major research goal of medicinal chemistry is to design completely non-peptide scaffolds that mimic the topography and function of peptide-derived inhibitors. Researchers at Roche-Basel recently discovered novel topographical peptidomimetic inhibitors of the aspartic peptidases renin and plasmepsin based on a piperidine scaffold [1]. The aspartic peptidases are the current therapeutic targets for a variety of human diseases including AIDS, Alzheimer’s disease, hypertension, and malaria. Consequently, the screening-based discovery of these non-peptide peptidomimetics constitutes a major advance for the development of medicinal compounds to treat these disease states. We have used the structure-generating program Growmol [2] to rationally design the related piperidine analogs 1 and 2 (Figure 1) that inhibit Rhizopus chinensis and porcine pepsin (IC50 2 and 0.2 µM, respectively), two aspartic peptidases not inhibited in the Roche reports. We developed enantioselective syntheses of the piperidine scaffolds as well as a solid supported traceless functionalization method to provide quick access to analogs of these non-peptide peptidomimetic inhibitors.