Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors

摘要: Abstract Background: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use combination with other antiviral agents inhibit development resistance. The daunting ability virus rapidly generate resistant mutants suggests there an ongoing need for new superior pharmacokinetic and efficacy profiles. In our attempts design select improved cyclic urea inhibitors, we simultaneously optimized potency, resistance profile, protein binding oral bioavailability. Results: We discovered nonsymmetrical ureas containing a 3-aminoindazole P2 group potent excellent Furthermore, forms four hydrogen bonds enzyme imparts good profile. 3-aminoindazoles DMP 850 851 were selected as next generation because they achieve 8 h trough blood levels dog, 10 mg/kg dose, at or above protein-binding-adjusted IC 90 value worst single mutant — Ile84→4Val mutation. Conclusions: selecting established rigorous set criteria designed maximize chances sustained effect HIV-infected individuals. As provide plasma free drug sufficient wild-type several HIV, could show decrease viral load clinically significant time periods. ultimate success might depend on achieving exceeding bioavailability seen dog.