Background: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. Results: We have synthesized DMP 450 (his-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of IO mg kg-t DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in viva assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC,, suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. Conclusions: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.

The pharmacokinetics of a series of novel cyclic, non-peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90 values of 0.03-1.0 microM (0.017-0.76 microgram mL-1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21-1.88 micrograms mL-1 were detected within 1 h of oral administration of 10 mg kg-1 of the compounds. The elimination half-lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 micrograms mL-1 and 48%, 1.07 micrograms mL-1 and 16%, and 1.48 mg ML-1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90 for inhibition of viral replication after single doses of 10 mg kg-1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV-associated diseases.