A Novel Prodrug Strategy Based on Reversibly Degradable Guanidine Imides for High Oral Bioavailability and Prolonged Pharmacokinetics of Broad-Spectrum Anti-influenza Agents.

We present orally administrable prodrugs ( OSC-GCDI s) of guanidino oseltamivir carboxylate ( GOC ) based on guanidine cyclic diimide (GCDI) to treat influenza viruses. By concealing the guanidine group, which significantly limits the intestinal absorption, its prodrugs OSC-GCDI s demonstrate dramatic improvement of oral bioavailability. The most promising antiviral substance OSC-GCDI(P) readily forms covalent adducts with serum proteins via a degradable linker after the intestinal absorption. Subsequently, the active species, GOC , is released from the conjugate in a sustained manner, which greatly contributes to improving pharmacokinetic properties. Because of the remarkable improvements in both oral bioavailability and longevity of its active metabolite, OSC-GCDI(P) demonstrates outstanding therapeutic efficacy against both wild-type and oseltamivir-resistant (H275Y) influenza virus strains in a mouse infection model, even with a single oral administration.