In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates

Abstract

PNU-140690 (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone) is a potent, nonpeptidic inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease currently under clinical evaluation. PNU-140690 and ritonavir were studied in two-drug combinations against the replication of HIV-1 clinical isolates in peripheral blood mononuclear cells. A ritonavir-sensitive (301-1x) and -resistant (301-6x) isolate pair derived from an individual before and after monotherapy with ritonavir were used. These isolates showed no significant difference in sensitivity to PNU-140690, but isolate 301-6x was more than 50-fold less sensitive to ritonavir than isolate 301-1x. Mathematical analysis showed that the combination of various concentrations of PNU-140690 with ritonavir yielded additive to moderately synergistic antiviral effects against the ritonavir-sensitive isolate and stronger synergy against the ritonavir-resistant isolate. The mechanism of synergy was not investigated, but the results suggested that both the virological and the observed in vitro pharmacological effects may have contributed to the observed synergy. Importantly, no significant antagonism was observed with the drug combinations studied. These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protease inhibitor such as ritonavir.

Recent progress in the development of coumarin derivatives as potent anti‐HIV agents

“…However, with both monomethylation and methoxylation, substitution at the position 6 (54 and 58, respectively) dramatically decreased the activity. Analogs with other substituents, such as propyl (59), isopropyl (60), phenyl (61), and trifluoromethyl (62), at position 4 were less potent or inactive. The extremely high anti-HIV potency of 4-methyl-DCK (52) and 5-methyl-DCK (53) indicates that a methyl group on the coumarin ring probably fits well into a hydrophobic cleft on the target's active surface and greatly increases both the agent's target affinity and the desired pharmacological response.…”

“…59,60 Further QSAR studies have lead to discovery of a sufonamidecontaining 5,6-dihydro-4-hydroxy-2-pyrone, also called tipranavir (130), which is currently undergoing phase II clinical trial. [60][61][62][63]…”

Practical Perspectives on the Use of Tipranavir in Combination With Other Medications: Lessons Learned From Pharmacokinetic Studies

“…[5][6][7] Like many PIs, tipranavir is taken concomitantly with ritonavir. Because ritonavir inhibits CYP3A, 8,9 the combination results in a boost in tipranavir plasma concentrations. Consequently, clinically useful plasma concentrations of tipranavir can be achieved with an acceptable pill burden-two 250-mg capsules of tipranavir twice a day, plus two 250-mg capsules of ritonavir also twice daily.…”

New drugs for the treatment of HIV infection

“…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].…”