1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

NEW CYCLIC UREA-BASED PROTEASE INHIBITORS WITH IMPROVED POTENCY, ORAL BIOAVAILABILITY AND RESISTANCE PROFILES

Antiviral Therapy 1997;2 (Suppl 5):1 (abstract no. 2)

Lee T Bacheler, James D Rodgers, Patrick YS Lam, Matt Wright, Sean Garber, Carol Reid and Sue Erickson-Viitanen
DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, DE 19880-0336, USA

The ability of an administered drug to provide clinical benefit when the drug target is an intracellular enzyme is a property of the drug's potency, pharmacokinetic profile and availability of free drug for diffusion across the target cell membrane. Thus, prediction of the overall quality of an AIDS therapeutic must consider absolute potency towards both wild-type and mutant variants likely to pre-exist in the treated population, as well as pharmacokinetic properties and the extent of plasma protein binding. We have combined these considerations into the concept of PPPP, the ‘potency, protein binding, pharmacokinetics parameter’, in which we compare the trough level resulting from a given dosing regimen to the protein binding-adjusted IC₉₀ for wild-type and single mutant variants of HIV-1.

DMP 850 and DMP 851 are asymmetric cyclic ureas with indazole P2′ groups. They are potent inhibitors of HIV protease and of HIV-1 virus replication in cell culture. In comparison to DMP 450, a first generation cyclic urea-based inhibitor of HIV-1 protease, both are more potent antivirals against wild-type laboratory strains and clinical isolates, and against some single amino acid variants (82F and 84V) of HIV. In addition, each shows a smaller loss of potency against multiply mutated viruses resistant to ritonavir, indinivir, saquinivir and VX-478 than does DMP 450. Cell culture selection experiments suggest that in vitro emergence of viruses resistant to DMP 850 and DMP 851 may be delayed relative to emergence of resistance to DMP 450. The effect of binding to human plasma proteins was assessed in cell culture assays of antiviral potency. Inclusion of 45 mg/ml HSA and 1.0 mg/ml AAG in the culture medium causes an eight-fold loss of potency for DMP 450, a 9.5-fold loss for DMP 850, and a 21.6-fold loss for DMP 851. Pharmacokinetic studies of plasma levels in dogs after a single 10 mg/kg oral dose reveal 8 h trough levels of inhibitor which meet or exceed the protein binding-adjusted IC₉₀ of wild-type and single amino acid mutants of HIV. The combination of these properties into a PPPP suggests that DMP 850 and DMP 851 each represent an attractive candidate for further development. Safety assessment studies are currently in progress.

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1997-06-25
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