8th Conference on Retroviruses and Opportunistic Infections Chicago, IL - February 4 - 8, 2001

Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:46 (abstract no. 11)

S. Erickson-Viitanen¹, R. Kaltenbach¹, D. Getman², S. Garber¹, K. Logue¹, S. Jeffrey¹, L. Bacheler¹, S. Diamond¹, A. Albright³, F. Gonzalez-Scarano³, M. Davies¹, G. Harris¹, and G. Trainor^1
1DuPont Pharmaceuticals Co., Wilmington, DE; ²Monsanto Co., St. Louis, MO (now Pharmacia Corp.); and ³Univ. of Pennsylvania, Philadelphia.

BACKGROUND: HIV protease inhibitors (PIs) are important components of many HAART regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross- resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at trough.

METHODS: A series of substituted sulfonamides was evaluated against lab strains and clinical isolates of HIV-1 in several cell types, including viruses with mutations in the protease gene. Serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC₉₀).

RESULTS: DPC 681 and DPC 684 are potent inhibitors of HIV protease (K_i @ 10-20 pM) with 90% inhibitory concentrations (IC₉₀) for wild-type HIV-1 of 4-8 nM. IC₉₀ values for neurotropic isolates replicating in microglia were approximately 20 nM. Potency was retained across non-clade-B isolates. DPC 681 and DPC 684 showed no loss in potency towards mutant HIVs with the D30N mutation and 5-fold or smaller loss in potency towards variants with 3-5 amino acid substitutions. Chimeric viruses constructed from clinical samples from patients who have failed PI-containing regimens and containing 6 or 7 mutations including positions 10, 63, 71, 82, 84 and 90 showed a 3- to 6-fold loss in sensitivity to DPC 681 or DPC 684. In contrast, these mutant variants showed a 13-190-fold loss in sensitivity to other HIV protease inhibitors. DPC 681 and DPC 684 have plasma free fractions of 1.6 and 1.9%. respectively. so that total (protein-binding adjusted) drug at trough of 1000 nM is predicted to yield 90% suppression of the variants assessed to date.

CONCLUSIONS: Second generation PIs DPC 681 and DPC 684 are potent inhibitors of wild type and resistant virus variants. Plasma levels required for suppression of replication of even highly mutated HIV are less than 1 micromolar. Phase I studies with both analogs have been initiated.

2001-02-04
11

Copyright © 2001 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.