title: TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1.
abstract: 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 microM). 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 alpha1-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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Hilde
authors.initials: H
authors.lastname: Azijn
authors.forename: Theo
authors.initials: T
authors.lastname: Thielemans
authors.forename: Donald
authors.initials: D
authors.lastname: Ludovici
authors.forename: Michael
authors.initials: M
authors.lastname: Kukla
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: Paul
authors.initials: P
authors.lastname: Janssen
authors.forename: Bart
authors.initials: B
authors.lastname: De Corte
authors.forename: Johan
authors.initials: J
authors.lastname: Vingerhoets
authors.forename: Rudi
authors.initials: R
authors.lastname: Pauwels
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Béthune
mesh_terms: D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009570:Nitriles; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine