Prodrugs of Neuraminidase Inhibitors for Increased Oral Bioavailability

DESCRIPTION (provided by applicant): Virally-encoded neuraminidase plays a key role in the life-cycle of the influenza virus. A class of anti-influenza drugs that inhibits the action of neuraminidase has garnered increasing interest in the pharmaceutical industry due to their selectivity and potency. The inhibitors are transition state analogs of the enzyme substrate, sialic acid, and are highly efficacious in in vitro and in vivo studies, with IC50 values in the nM range. However these drugs are very polar and consequently have poor oral bioavailability. At TSRL, we have a developed an amino acid prodrug strategy that targets intestinal transporters for enhanced uptake. Subsequent activation of the absorbed prodrug can then occur either through targeted enzymatic hydrolysis of the prodrug or chemical breakdown of the prodrug to the activate parent compound. This strategy is based on a molecular mechanistic understanding of the transport and activation pathways in cells and tissues and the interaction of prodrug structures with these pathways. In this proposal, we have developed novel amino acid acyloxy ester prodrugs of two neuraminidase inhibitors and provide strong preliminary data showing that these prodrugs are actively transported by intestinal transporter and have good intestinal permeability in an in situ intestinal permeability model. We hypothesize that through this prodrug approach, we can boost the oral availability of selected neuraminidase inhibitors to an extent that they can be developed as oral drug products. In the current project, we propose to fully characterize a series of these prodrugs with regard to their stability, tissue activation, and bioavailability. Compounds showing acceptable characteristics will be tested for in vivo efficacy against the H1N1 virus by the NIAID contract facility at Utah State University. Our molecular mechanistic approach to prodrug design has enormous potential for the development of orally effective neuraminidase inhibitors. More broadly, this prodrug strategy offers great potential and much promise in reaching the ultimate goal of developing viable oral alternatives for a wider range of therapeutically potent antiviral agents. PUBLIC HEALTH RELEVANCE: TSRL has developed an approach to improve the oral bioavailability of anti-influenza drugs, thus making them suitable for oral delivery. We propose to synthesize and test a series of these compounds for their potential as oral agents. Ultimately, this approach may increase the number of potent anti-virus compounds that are available for therapeutic and prophylactic treatment of influenza.