Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains

Mordant, Céline; Schmitt, Benoît; Pasquier, Elisabeth; Demestre, Christophe; Quéguiner, Laurence; Masungi, Chantal; Peeters, Anik; Smeulders, Liesbeth; Bettens, Eva; Hertogs, Kurt; Heeres, Jan; Lewi, Paul; Guillemont, Jérôme

doi:10.1016/j.ejmech.2006.11.014

Cited by 64 publications

(35 citation statements)

References 16 publications

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“…Etravine (TMC125) has an in vitro resistance profile superior to that of dapivirine and has demonstrated efficacy for NNRTI-resistant patients (24,28). Rilpivirine (TMC278) also has a better in vitro resistance profile than dapivirine and has recently entered phase III clinical development with antiretroviral-therapy-naïve patients (33,41). While these newer drugs have promising activities against NNRTIresistant HIV-1, their activities against wild-type HIV-1 are similar to that of dapivirine (1,2,25,33).…”

Section: Discussionmentioning

confidence: 99%

“…Rilpivirine (TMC278) also has a better in vitro resistance profile than dapivirine and has recently entered phase III clinical development with antiretroviral-therapy-naïve patients (33,41). While these newer drugs have promising activities against NNRTIresistant HIV-1, their activities against wild-type HIV-1 are similar to that of dapivirine (1,2,25,33). Their development as microbicides in preference to dapivirine would require significant preclinical (formulation, toxicity, pharmacology) and early clinical safety studies before they could be evaluated in efficacy trials, with no guarantee that they might not fail at any stage in the development process.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor

Fletcher

Harman

Azijn³

et al. 2009

Antimicrob Agents Chemother

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Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor

Fletcher

Harman

Azijn³

et al. 2009

Antimicrob Agents Chemother

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“…Rilpivirine (TMC278), a diarylpyrimidine derivative, is a next-generation NNRTI currently in development as an oral formulation for the treatment of HIV, showing an improved resistance profile against NNRTI-resistant HIV-1. In vitro, it was shown to have a more pronounced activity against both wild-type and resistant HIV-1 strains, with an increased genetic barrier to viral resistance compared to the first-generation NNRTIs (19). The in vitro 50% effective concentration (EC 50 ) for wild-type HIV virus is 0.51 nM (0.18 ng/ml) (10).…”

mentioning

confidence: 99%

Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation

Klooster¹,

Hoeben²,

Borghys³

et al. 2010

Antimicrob Agents Chemother

178

113

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The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentrationtime profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3-to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.

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“…167 Replacing the triazine ring of DATA by a pyrimidine ring led to the DAPY (diarylpyrimidine) compounds, 168 first TMC 120 (which is currently being pursued for its microbicidal potential), then TMC 125 (etravirine), 169 which has since January 18, 2008 been approved [Intelence s , Tibotec Therapeutics, Bridgewater, NJ] and, finally, rilpivirine (R278474, TMC 278) 170 which, according to van Roey et al, 171 is now entering phase III clinical trials at a daily dosage of 25 mg (orally), and, in the meantime, slightly modified versions of rilpivirine (with a chlorine replacing one of the methyl groups) have been constructed. 172 The route from TIBO (tivirapine) to TMC 278 (rilpivirine) spans two decades of medicinal chemistry research , as depicted in Figure 9A. The newer derivatives, etravirine (TMC 125) and rilpivirine (TMC 278), as compared to the older ones, show remarkably higher activity against HIV-1 variants carrying the signature NNRTI resistance mutations K103N or double mutations K103N1Y181C.…”

Section: The Long Route From Tibo (Tivirapine) To Rilpivirine (Tmc 27mentioning

confidence: 98%

Another ten stories in antiviral drug discovery (part C): “Old” and “new” antivirals, strategies, and perspectives

Clercq

2009

Medicinal Research Reviews

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The ten stories told here deal with (i) ribavirin as an inhibitor of IMP dehydrogenase and (ii) ribavirin, in combination with pegylated interferon, as the present "standard of care" for hepatitis C; (iii) S-adenosylhomocysteine hydrolase inhibitors as antiviral agents; (iv) new adamantadine derivatives for the treatment of influenza A virus infections; (v) 5-substituted 2'-deoxyuridines (i.e. IDU, TFT) for the treatment of herpes simplex virus (HSV) infections; (vi) acyclic guanosine analogues (e.g. acyclovir) for the treatment of HSV infections; (vii) OMP decarboxylase inhibitors (i.e. pyrazofurin) and CTP synthetase inhibitors (i.e. cyclopentenylcytosine) as possible antiviral agents; (viii) the future of cidofovir (and alkoxyalkyl esters thereof) and ST-246 as potential antipoxvirus agents; (ix) the two decade journey from tivirapine to rilpivirine in the ultimate therapy of HIV infections; and (x) the extension of the therapeutic application of tenofovir disoproxil fumarate (Viread) to the treatment of hepatitis B virus infection, in addition to HIV infection.

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Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains

Cited by 64 publications

References 16 publications

Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor

Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor

Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation

Another ten stories in antiviral drug discovery (part C): “Old” and “new” antivirals, strategies, and perspectives

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