Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor

Abstract

PNU-140690 is a member of a new class of nonpeptidic human immunodeficiency virus (HIV) protease inhibitors (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones) discovered by structure-based design. PNU-140690 has excellent potency against a variety of HIV type 1 (HIV-1) laboratory strains and clinical isolates, including those resistant to the reverse transcriptase inhibitors zidovudine or delavirdine. When combined with either zidovudine or delavirdine, PNU-140690 contributes to synergistic antiviral activity. PNU-140690 is also highly active against HIV-1 variants resistant to peptidomimetic protease inhibitors, underscoring the structural distinctions between PNU-140690 and substrate analog protease inhibitors. PNU-140690 retains good antiviral activity in vitro in the presence of human plasma proteins, and preclinical pharmacokinetic studies revealed good oral bioavailability. Accordingly, PNU-140690 is a candidate for clinical evaluation.

Second generation HIV protease inhibitors against resistant virus

“…It was approved by the FDA in 2005. However, data from Phase II and III clinical trials in which TPV/r was used as part of salvage therapy in patients failing other protease inhibitors also showed that a broader range of mutations developed [55,56] .…”

New drugs for the treatment of HIV infection

“…Another study demonstrated the activity of tipranavir against clinical viral isolates with resistance to indinavir, ritonavir, and nelfinavir (IC 50 ≥ 0.1 µmol/L) [20]. Tipranavir has also demonstrated activity against viral isolates resistant to zidovudine or delavirdine and has shown synergistic activity when used in combination with either zidovudine or delavirdine [21]. An in vitro study of tipranavir and ritonavir in combination demonstrated additive to moderate synergistic activity against a ritonavirsensitive isolate, and even greater synergy against a ritonavir-resistant isolate [22].…”

Potential New Therapies for the Treatment of HIV-1 Infection

“…Tipranavir (TPV), discovered by researchers at Pharmacia-Upjohn and now being developed by Boehringer-Ingelheim, has a nonpeptidyl structure whose interaction with the protease depends less on the amino acid side-chains of the protease than those of earlier PIs (11,12). Accordingly, the inhibition of the protease by TPV is less affected by many amino acid substitutions that confer significant resistance to other PIs (13).…”