Synergistic Inhibition of Human Immunodeficiency Virus Type 1 Replication <i>in Vitro</i> by Two- and Three-Drug Combinations of Delavirdine, Lamivudine and Zidovudine

Pyrido [1,2a] indole derivatives were identified as potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication during a random screening programme. The compounds showed no antiviral activity against HIV-2 or in cells chronically infected with HIV-1, but had good inhibitory effect against purified HIV-1 reverse transcriptase (RT) in an in vitro assay. They were therefore classified as nonnucleoside RT inhibitors (NNRTI). The synthesis of additional compounds of the same class revealed a structure—activity relationship. The most potent compound of the series, BCH-1, had similar antiviral activity to the licensed NNRTI nevirapine against laboratory strains of HIV-1 cultured in cell lines and primary clinical isolates of HIV-1 cultured in peripheral blood mononuclear cells. However, BCH-1 showed greater cytotoxicity, providing a narrow selectivity index in the order of 35. BCH-1 had equivalent antiviral activity against viruses resistant to the nucleoside RT inhibitors zidovudine, didanosine and lamivudine and maintained better activity (less than threefold change in IC50) than nevirapine against viruses resistant to a range of NNRTIs with the single amino acid changes L100I, K103N, E138K or Y181C in the RT. Viruses with single V106A or Y188C amino acid changes showed five- and 10-fold resistance to BCH-1, respectively, in contrast to nevirapine, which had a >100-fold change in IC50. However, virus with both V106A and Y188C amino acid changes showed higher level resistance (>15-fold) to BCH-1. Virus with >10-fold resistance to BCH-1 was rapidly selected for after growth in increasing concentrations of compound and was shown to be cross-resistant to nevirapine. Sequencing of this virus revealed two amino acid changes at positions 179 (V to D) and 181 (Y to C) in the RT. BCH-1 represents a new class of NNRTI, which may act as a lead to identify more selective compounds.

show abstract

Delavirdine

Scott¹,

Perry²

2000

Drugs

View full text Add to dashboard Cite

In combination with NRTIs. delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.

show abstract

Synergistic Inhibition of Human Immunodeficiency Virus Type 1 Replication in Vitro by Two- and Three-Drug Combinations of Delavirdine, Lamivudine and Zidovudine

Cited by 3 publications

References 34 publications

Delavirdine

Delavirdine

Pyrido [1,2a] Indole Derivatives Identified as Novel Nonnucleoside Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Type 1

Delavirdine

Contact Info

Product

Resources

About