DESIGN AND SELECTION OF DMP-850 AND DMP-851 - THE NEXT-GENERATION OF CYCLIC UREA HIV PROTEASE INHIBITORS

Background: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, howe ver, to use HIV protease inhibitors in combination with other antivira l agents to inhibit the development of resistance. The daunting abilit y of the virus to rapidly generate resistant mutants suggests that the re is an ongoing need for new HIV protease inhibitors with superior ph armacokinetic and efficacy profiles. In our attempts to design and sel ect improved cyclic urea HIV protease inhibitors, we have simultaneous ly optimized potency, resistance profile, protein binding and oral bio availability. Results: We have discovered that nonsymmetrical cyclic u reas containing a 3-aminoindazole P2 group are potent inhibitors of HI V protease with excellent oral bioavailability. Furthermore, the 3-ami noindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 85 0 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in do g, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant - that containing the lle84-->Val m utation.Conclusions: In selecting our next generation of cyclic urea H IV protease inhibitors, we established a rigorous set of criteria desi gned to maximize chances for a sustained antiviral effect in HIV-infec ted individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant f orms of HIV, they could show improved ability to decrease viral load f or clinically significant time periods. The ultimate success of DMP 85 0 and DMP 851 in clinical trials might depend on achieving or exceedin g the oral bioavailability seen in dog.