This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andries, K. Articles by de Béthune, M.-P. Search for Related Content PubMed PubMed Citation Articles by Andries, K. Articles by de Béthune, M.-P.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2004, p. 4680-4686, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4680-4686.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

TMC125, a Novel Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor Active against Nonnucleoside Reverse Transcriptase Inhibitor-Resistant Human Immunodeficiency Virus Type 1

Johnson & Johnson Pharmaceutical Research and Development, Beerse,¹ Tibotec, Mechelen,² Johnson & Johnson Pharmaceutical Research and Development, Vosselaar, Belgium,⁴ Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania³

Received 9 April 2004/ Returned for modification 27 May 2004/ Accepted 5 August 2004

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC₅₀] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC₅₀ = 3.5 µM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). 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 ₁-acid glycoprotein/ml, or 50% human serum. 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. TMC125 also retained activity (EC₅₀ < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.

This article has been cited by other articles:

• Llibre, J. M., Santos, J. R., Puig, T., Molto, J., Ruiz, L., Paredes, R., Clotet, B. (2008). Prevalence of etravirine-associated mutations in clinical samples with resistance to nevirapine and efavirenz. J Antimicrob Chemother 62: 909-913 [Abstract] [Full Text]  
• Geretti, A. M. (2008). Shifting paradigms: the resistance profile of etravirine. J Antimicrob Chemother 62: 643-647 [Abstract] [Full Text]  
• Peeters, M., Janssen, K., Kakuda, T. N, Scholler-Gyure, M., Lachaert, R., Hoetelmans, R. M., Woodfall, B., De Smedt, G. (2008). Etravirine Has No Effect on QT and Corrected QT Interval in HIV-Negative Volunteers. The Annals of Pharmacotherapy 42: 757-765 [Abstract] [Full Text]  
• Scholler-Gyure, M., van den Brink, W., Kakuda, T. N., Woodfall, B., De Smedt, G., Vanaken, H., Stevens, T., Peeters, M., Vandermeulen, K., Hoetelmans, R. M. W. (2008). Pharmacokinetic and Pharmacodynamic Study of the Concomitant Administration of Methadone and TMC125 in HIV-Negative Volunteers. J Clin Pharmacol 48: 322-329 [Abstract] [Full Text]  
• Poveda, E., Garrido, C., de Mendoza, C., Corral, A., Cobo, J., Gonzalez-Lahoz, J., Soriano, V. (2007). Prevalence of etravirine (TMC-125) resistance mutations in HIV-infected patients with prior experience of non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 60: 1409-1410 [Full Text]  
• Aquaro, S., Svicher, V., Schols, D., Pollicita, M., Antinori, A., Balzarini, J., Perno, C. F. (2006). Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies. J. Leukoc. Biol. 80: 1103-1110 [Abstract] [Full Text]  
• Hazen, R. J., Harvey, R. J., St. Clair, M. H., Ferris, R. G., Freeman, G. A., Tidwell, J. H., Schaller, L. T., Cowan, J. R., Short, S. A., Romines, K. R., Chan, J. H., Boone, L. R. (2005). Anti-Human Immunodeficiency Virus Type 1 Activity of the Nonnucleoside Reverse Transcriptase Inhibitor GW678248 in Combination with Other Antiretrovirals against Clinical Isolate Viruses and In Vitro Selection for Resistance. Antimicrob. Agents Chemother. 49: 4465-4473 [Abstract] [Full Text]  
• Vingerhoets, J., Azijn, H., Fransen, E., De Baere, I., Smeulders, L., Jochmans, D., Andries, K., Pauwels, R., de Bethune, M.-P. (2005). TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments. J. Virol. 79: 12773-12782 [Abstract] [Full Text]  
• Ferris, R. G., Hazen, R. J., Roberts, G. B., St. Clair, M. H., Chan, J. H., Romines, K. R., Freeman, G. A., Tidwell, J. H., Schaller, L. T., Cowan, J. R., Short, S. A., Weaver, K. L., Selleseth, D. W., Moniri, K. R., Boone, L. R. (2005). Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor. Antimicrob. Agents Chemother. 49: 4046-4051 [Abstract] [Full Text]  
• Mulky, A., Kappes, J. C. (2005). Analysis of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Subunit Structure/Function in the Context of Infectious Virions and Human Target Cells. Antimicrob. Agents Chemother. 49: 3762-3769 [Abstract] [Full Text]