ABSTRACT
The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC(50)s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC(50) of < or =21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC(50) of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml alpha-1 acid glycoprotein increased the IC(50) approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.
Subject(s)
Anti-HIV Agents/pharmacology , Antiviral Agents/pharmacology , Benzophenones/chemistry , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/therapeutic use , Antiviral Agents/therapeutic use , Cell Culture Techniques , Cell Line, Tumor , Cells, Cultured , Cytotoxicity Tests, Immunologic , Drug Evaluation, Preclinical , Drug Resistance, Viral , HIV-1/genetics , HeLa Cells , Humans , Inhibitory Concentration 50 , Jurkat Cells , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/virology , Molecular Structure , Mutation , Orosomucoid/metabolism , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/therapeutic use , Serum Albumin/metabolism , U937 Cells , Virus Replication/drug effectsABSTRACT
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.
Subject(s)
Anti-HIV Agents/chemical synthesis , Drug Resistance, Viral , HIV Reverse Transcriptase/chemistry , Quinolones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Alkynes , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzoxazines , Binding Sites , Cell Line , Crystallography, X-Ray , Cyclopropanes , Drug Design , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , Humans , Models, Molecular , Molecular Structure , Mutation , Oxazines/chemistry , Quinolones/chemistry , Quinolones/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
GW4511, GW4751, and GW3011 showed IC50 values < or =2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.
