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Chemical Compound Review

Intelence     4-[6-amino-5-bromo-2-[(4...

Synonyms: Etravirine, Intelence(TM), Intelence (TN), cc-89, PubChem22565, ...
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Disease relevance of DAPY deriv

  • TMC 125 was studied in HIV-1 infected patients with high-level phenotypic NNRTI resistance in an open-label phase IIa trial [1].
  • TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs [2].

High impact information on DAPY deriv

  • MAIN OUTCOME MEASURES: Change in plasma HIV-1 RNA from baseline values (primary); change in CD4 cell counts from baseline, and evaluation of safety, tolerability and pharmacokinetics of TMC125 treatment (secondary) [3].
  • We assessed the short-term efficacy and safety of a next generation NNRTI, TMC 125, a diarylpyrimidine derivative that has in vitro activity against NNRTI resistant HIV-1 [1].
  • We compared the initial rate of decline of plasma HIV-1 RNA achieved by TMC125 monotherapy with that of a triple class, five-drug regimen, containing drugs from all three currently licensed classes (zidovudine, lamivudine, abacavir, indinavir and nevirapine) [4].
  • RESULTS: Median ages were 23 and 38 years for TMC125 and ERA patients, respectively (P = 0.001), median baseline plasma HIV-1 RNA levels were 4.2 and 4.8 log10 copies/ml (P = 0.001) and median baseline CD4 T-cell counts were 458 x 10(6) and 360 x 10(6) cells/l (P = 0.08) [4].
  • Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine [2].

Chemical compound and disease context of DAPY deriv


Biological context of DAPY deriv

  • OBJECTIVE: To evaluate antiviral activity, tolerability, safety and pharmacokinetics of treatment with TMC125 (a non-nucleoside reverse transcriptase inhibitor), 900 mg twice daily for 7 days [3].
  • In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C [7].

Associations of DAPY deriv with other chemical compounds

  • A newer generation NNRTI, TMC125, showed potency (55 nM) against WT and all mutants, paralleling the activity of this inhibitor relative to nevirapine and efavirenz in cell culture [8].
  • Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of alpha1-acid glycoprotein/ml, or 50% human serum [7].
  • Of several NNRTIs that are in preclinical and clinical development, two agents, capravirine and TMC125, have shown promise in early clinical trials [9].
  • Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor [10].

Gene context of DAPY deriv


Analytical, diagnostic and therapeutic context of DAPY deriv

  • Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants [12].
  • TMC-125 is currently in phase III clinical trials and on track to become the first NNRTI suitable for use in NNRTI-experienced patients [13].


  1. An open-label assessment of TMC 125--a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. Gazzard, B.G., Pozniak, A.L., Rosenbaum, W., Yeni, G.P., Staszewski, S., Arasteh, K., De Dier, K., Peeters, M., Woodfall, B., Stebbing, J., vant' Klooster, G.A. AIDS (2003) [Pubmed]
  2. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. Vingerhoets, J., Azijn, H., Fransen, E., De Baere, I., Smeulders, L., Jochmans, D., Andries, K., Pauwels, R., de Béthune, M.P. J. Virol. (2005) [Pubmed]
  3. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. Gruzdev, B., Rakhmanova, A., Doubovskaya, E., Yakovlev, A., Peeters, M., Rinehart, A., de Dier, K., Baede-Van Dijk, P., Parys, W., van 't Klooster, G. AIDS (2003) [Pubmed]
  4. TMC125 exerts similar initial antiviral potency as a five-drug, triple class antiretroviral regimen. Sankatsing, S.U., Weverling, G.J., Peeters, M., van't Klooster, G., Gruzdev, B., Rakhmanova, A., Danner, S.A., Jurriaans, S., Prins, J.M., Lange, J.M. AIDS (2003) [Pubmed]
  5. Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Balzarini, J. Current topics in medicinal chemistry. (2004) [Pubmed]
  6. Potent Nonnucleoside Reverse Transcriptase Inhibitors Target HIV-1 Gag-Pol. Figueiredo, A., Moore, K.L., Mak, J., Sluis-Cremer, N., de Bethune, M.P., Tachedjian, G. PLoS Pathog. (2006) [Pubmed]
  7. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Andries, K., Azijn, H., Thielemans, T., Ludovici, D., Kukla, M., Heeres, J., Janssen, P., De Corte, B., Vingerhoets, J., Pauwels, R., de Béthune, M.P. Antimicrob. Agents Chemother. (2004) [Pubmed]
  8. Modulation of human immunodeficiency virus type 1 synergistic inhibition by reverse transcriptase mutations. Basavapathruni, A., Vingerhoets, J., de Béthune, M.P., Chung, R., Bailey, C.M., Kim, J., Anderson, K.S. Biochemistry (2006) [Pubmed]
  9. New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Pauwels, R. Current opinion in pharmacology. (2004) [Pubmed]
  10. Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. Boffito, M., Winston, A., Jackson, A., Fletcher, C., Pozniak, A., Nelson, M., Moyle, G., Tolowinska, I., Hoetelmans, R., Miralles, D., Gazzard, B. AIDS (2007) [Pubmed]
  11. Substrate-dependent inhibition or stimulation of HIV RNase H activity by non-nucleoside reverse transcriptase inhibitors (NNRTIs). Hang, J.Q., Li, Y., Yang, Y., Cammack, N., Mirzadegan, T., Klumpp, K. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  12. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. Das, K., Clark, A.D., Lewi, P.J., Heeres, J., De Jonge, M.R., Koymans, L.M., Vinkers, H.M., Daeyaert, F., Ludovici, D.W., Kukla, M.J., De Corte, B., Kavash, R.W., Ho, C.Y., Ye, H., Lichtenstein, M.A., Andries, K., Pauwels, R., De Béthune, M.P., Boyer, P.L., Clark, P., Hughes, S.H., Janssen, P.A., Arnold, E. J. Med. Chem. (2004) [Pubmed]
  13. Next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors. Boone, L.R. Current opinion in investigational drugs (London, England : 2000) (2006) [Pubmed]
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