Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones

Hargrave, Karl D.; Proudfoot, John; Grozinger, Karl; Cullen, Ernest; Kapadia, Suresh; Patel, Usha; Fuchs, V.; Mauldin, Scott C.; Vitous, Jana; Behnke, Mark L.; Klunder, Janice M.; Pal, Kollol; Skiles, Jerry W.; McNeil, Daniel W.; Rose, Janice; Chow, Grace C.; Skoog, Mark T.; Wu, Joe C.; Schmidt, Günther; Engel, Wolfhard; Eberlein, Wolfgang; Saboe, Tracy D.; Campbell, Scot; Rosenthal, Alan S.; Adams, Julian

doi:10.1021/jm00111a045

Cited by 201 publications

(88 citation statements)

References 28 publications

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“…NVP was kindly supplied by Boehringer-Ingelheim GmbH. 12-OH-NVP (Grozinger et al, 1995), 12-Cl-NVP (Kelly et al, 1995), and 4-Cl-NVP (Hargrave et al, 1991;Norman et al, 2000) were synthesized as described previously. Phosphate-buffered saline (pH 7.4, fetal bovine serum (FBS), 1640 RPMI-HEPES modified, Eagle's minimal essential medium nonessential amino acids solution, and penicillin-streptomycin liquid were purchased from Invitrogen Canada, Inc. (Burlington, ON, Canada).…”

Section: Methodsmentioning

confidence: 99%

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Chen

Tharmanathan²,

Mannargudi³

et al. 2009

J Pharmacol Exp Ther

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Nevirapine treatment can cause a skin rash. We developed an animal model of this rash and determined that the 12-hydroxylation metabolic pathway is responsible for the rash, and treatment of animals with 12-OH-nevirapine also leads to a rash. In the present study, we investigated the specificity of lymphocytes in nevirapine-induced skin rash. Brown Norway rats were treated with nevirapine or 12-OH-nevirapine to induce a rash. Lymph nodes were removed, and the response of lymphocytes to nevirapine and its metabolites/analogs was determined by cytokine production (enzyme-linked immunosorbent assay, enzyme-linked immunosorbent spot assay, and Luminex) and proliferation (alamar blue assay). Subsets of lymphocytes were depleted to determine which cells were responsible for cytokine production. Lymphocytes from animals rechallenged with nevirapine proliferated to nevirapine, but not to 12-OH-nevirapine or 4-chloro-nevirapine. They also produced interferon-␥ (IFN-␥) when exposed to nevirapine, significantly less when exposed to 4-chloro-nevirapine, and very little when exposed to 12-OHnevirapine, even though oxidation to 12-OH-nevirapine is required to induce the rash. Moreover, the specificity of lymphocytes from 12-OH-nevirapine-treated rats was the same, i.e., responding to nevirapine more than to 12-OH-nevirapine, even though these animals had never been exposed to nevirapine. A Luminex immunoassay showed that a variety of other cytokines/chemokines were also produced by nevirapine-stimulated lymphocytes. CD4 ϩ cells were the major source of IFN-␥. The specificity of lymphocytes in activation assays cannot be used to determine what initiated an immune response. This has significant implications for understanding the evolution of an immune response and the basis of the pharmacological interaction hypothesis.Nevirapine (NVP), marketed under the trade name Viramune (Boehringer Ingelheim GmbH, Ingelheim, Germany), is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus infections. Although effective, its use has been limited because of its propensity to cause skin rash and liver toxicity. In patients, skin rashes vary from mild erythematous, maculopapular rashes to more severe Stevens-Johnson syndrome or toxic epidermal necrolysis (Warren et al., 1998;Fagot et al., 2001). Our group discovered a novel animal model of NVPinduced skin rash in rats. The characteristics of NVP-induced skin rash in Brown Norway rats are very similar to the milder rashes that occur in humans, which suggests that the mechanisms are very similar. Specifically, in both humans and rats there is a 2-to 3-week delay between starting the drug and the onset of rash, and on re-exposure, symptoms are more severe and accelerated (Shenton et al., 2003;Taiwo, 2006). Females are more susceptible to developing rash than males in both Brown Norway rats and humans. Furthermore, the sensitivity to NVP-induced skin rash can be transferred with CD4 ϩ T cells from NVP-rechallenged rats to naive recipients ...

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Section: Methodsmentioning

confidence: 99%

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Chen

Tharmanathan²,

Mannargudi³

et al. 2009

J Pharmacol Exp Ther

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“…AZT was purchased from Sigma Chemical Co. (St Louis, MO). Nevirapine and the pyridinome derivative 3-[2-(benzoxyazol-2-yl)ethyl]-5-ethyl-6-methylpyridine-2(1 H)-one (L-696229) were synthesized as described elsewhere (Hargrave et al, 1991;Mantlo et al, 1991). All compounds were dissolved in dimethyl sulfoxide and stored at -20°C until used.…”

Section: Materials and Experimental Procedures: Chemistrymentioning

confidence: 99%

Isolation and Characterization of Human Immunodeficiency Virus Type-1 Mutants Resistant to the Non-Nucleotide Reverse Transcriptase Inhibitor MKC-442

Seki

Sadakata²,

Yuasa³

et al. 1995

Antivir Chem Chemother

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MKC-442, 6-benzy 1-1-ethoxymethyl-5-isopropyIuraciI (l-EBU), is a potent and selective non-nucleoside inhibitor of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT). Nevirapine, another non-nucleoside RT inhibitor (NNRTI), is associated with rapid emergence of drug-resistant variants during in vitro passages of HIV-1. The emergence of resistant viruses to MKC-442 or nevirapine was examined in vitro. MT-4 cells infected with a clinical isolate (HE) of HIV-1 were cultivated in medium containing excess concentrations of these drugs, and the drug susceptibilities of the breakthrough viruses recovered from the medium were measured. Although nevirapine lost its antiviral activity after six passages, a delay in the emergence of fully resistant viruses was observed for MKC-442. Two resistant clones for each drug were isolated and nucleotide sequences within the RT region were analysed. An amino acid substitution at position 181 (Tyr to Cys) was found, with additional substitutions at positions 103 (Lys to Arg) and 108 (Val to lle) in the MKC-442-resistant viruses. These clones showed various susceptibilities to MKC-442, and cross-resistance to other NNRTIs but not to AZT. These results suggest that the major binding site of MKC-442 on the HIV-1 RT is the tyrosine residue common to these NNRTIs, and that drug resistance to NNRTIs is dependent on both the quality and the quantity of mutations within the HIV-1 RT gene.

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“…In the clinic, nevirapine (1, Figure 1) [7] monotherapy results in relatively rapid drug resistance due to mutation of the RT enzyme. In an effort to develop a second generation inhibitor with improved activity against mutant RT enzyme, a number of dipyridodiazepinone derivatives have been synthesized and evaluated their activities against HIV-1 RT enzymes [8].…”

Section: Introductionmentioning

confidence: 99%