AEGiS-13IAC: DPC 681 and DPC 684: Selective inhibitors of the Viral Protease active against resistant variants of HIV.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

DPC 681 and DPC 684: Selective inhibitors of the Viral Protease active against resistant variants of HIV.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrA532)

Erickson Viltanen S, Kaltenbach R, Getman D, Garber S, Jeffrey S, Bacheler L, Diamond S, Davies M, Trainor G
S. Erickson Viltanen, Dupont Pharmaceuticals, Ex Station - E336/228, PO Box 80336, Wilmington, DE 19880-0336, United States, Tel.: +1 302 695 7265, Fax: +1 302 695 3934, E-mail: susan.kerickson_viitanen@dupontpharma.com

INTRODUCTION: HIV Protease inhibitors (PIs) are important components of many HAART regimens. However, development of phenotypic and/or genotypic resistance can occur after months of therapy, including broad resistance to other inhibitors of this class. Development of resistance often occurs because trough levels of free drug are insufficient for significant inhibition of virus replication. There is thus a need for second-generation PIs, which are (1) more potent against wild type and mutant variants of HIV, (2) show higher levels of free drug at trough relative to required for significant inhibition of replication, (3) demonstrate improved tolerability profiles and (4) allow improved compliance.

METHODS: A series of substituted sulfonamides bearing P3 and P2' residue equivalents were evaluated against a panel of mutant viruses encoding one or more changes in the viral protease including V82F, I84V, D30N and I50V. In addition, binding to human serum proteins, and the pharmacokinetics and tolerability in the dog were determined.

RESULTS: DPC 681 and DPC 684 are inhibitors of purified HIV-1 protease, (Ki ~ 10-20 pM), and did not inhibit cellular aspartyl proteases, matrix metallo proteases, or serine proteases at concentrations > 10 m M. The concentrations yielding 90% inhibition of virus replication ranged from 5 nM for wild type HIV, to 50 nM for virus with five mutations (M46I/L63P/A71V/V82F/I84V). DPC 681 and DPC 684 showed no loss in activity virus carrying the D30N mutation, and only 4-fold to amprenavir-resistant virus carrying mutations at residues 46, 47 and 50. Considering plasma binding, a total drug concentration of 0.4 m M would be sufficient to yield é 90% inhibition of all wild type and mutant strains examined to date. Dogs given 30 mg/kg (po) of DPC 681 or DPC 684 had plasma drug concentrations exceeding those needed for antiviral efficacy for 4-6 hours. In preliminary safety studies, dogs tolerated single-oral doses of DPC 681 or DPC 684 of mg/kg and plasma concentrations of ~ 15-20 m M were achieved.

CONCLUSIONS: Second generation PIs DPC 681 and DPC 684 are potent inhibitors of wild type and highly mutated virus variants. Plasma levels required for suppression of replication of even highly mutated HIV are less than 0.5 m M. DPC 681 and DPC 684 have been selected for further development in Phase I single and multiple dose studies.

Keywords: AEGIS, HIV, Sulfonamides, HIV Protease Inhibitors, HIV Infections, HIV Protease, Virus Replication, Anti-HIV Agents, HIV Seropositivity, HIV-1 Reverse Transcriptase, Variation (Genetics), Mutation, DPC 681, DPC 684, VX 478, Dogs, Animal, Human, virology, genetics
000709
WeOrA532