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 [EC 50 ] ‫؍‬ 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC 50 ‫؍‬ 3.5 M). 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 EC 50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E؉K103N and K103N؉Y181C. TMC125 also retained activity (EC 50 < 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.Successful long-term treatment of human immunodeficiency virus type 1 (HIV-1) by antiretrovirals is often hindered by incomplete viral suppression and the resulting emergence of drug resistance. There is now widespread resistance to all available classes of antiretrovirals, and cross-resistance within classes is extensive, often severely limiting the treatment options available (17,20). Although currently marketed nonnucleoside reverse transcriptase inhibitors (NNRTIs) are highly selective and extremely potent, they rapidly select for resistant virus. Moreover, single mutations can lead to dramatic reductions in susceptibility, often to all available inhibitors within the class (2, 11). This broad cross-resistance prevents the consecutive use of currently marketed NNRTIs in treatment regimens (1). Next-generation agents with activity against NNRTI-resistant isolates would therefore offer new treatment options.To increase the likelihood of identifying new compounds active against NNRTI-resistant strains and that have interesting drug-like properties, we developed the following strategies. The structure-activity relationship, traditionally limited to activity against the wild-type virus, was expanded to include concurrent evaluation of several NNRTI-resistant strains. To facilitate...

Etravirine in combination with darunavir/ritonavir and optimized background regimen results in suppression of HIV replication in treatment-experienced patients

“…These results are maintained at 48 weeks. The results of this study also confirm the effectiveness of etravirine in individuals with underlying NNRTI resistance mutations, confirming earlier in vitro results [11].…”

“…This has been made a realistic outcome through the advent of new antiretrovirals that either target novel sites within the viral lifecycle (enfuvirtide, raltegravir and maraviroc) or are active despite resistance to first-generation antiretroviral agents [5][6][7][8][9]. The 'next-generation' antiretroviral agents include darunavir, a protease inhibitor active in the setting of underlying resistance to other protease inhibitors, and etravirine, a new non-nucleoside reverse transcriptase inhibitor (NNRTI), which retains activity against viruses demonstrating resistance to efavirenz and nevirapine [10,11]. The DUET studies assessed the clinical efficacy of etravirine compared with placebo, given in combination with a darunavir/ritonavir-containing optimized background regimen among treatment-experienced patients with documented HIV drug resistance and failing ongoing antiretroviral therapy.…”

Crystal structure of 6-oxo-4-propyl-2-(propylthio)-1,6-dihydropyrimidine-5-carbonitrile, C11H15N3OS

“…Non-nucleoside pyrimidine-based derivatives have long been known as potent anticancer drugs [1][2][3][4]. Large array of pyrimidine-based analogues have emerged as useful therapies against human immunode ciency viruses (HIV) [5][6][7][8], hepatitis B viruses (HBV) [9], herpes simplex viruses (HSV) [10,11], in uenza viruses [12] and varicella-zoster virus (VZV) [13]. Moreover, several pyrimidine derivatives were reported to display antibacterial [14][15][16][17] and antifungal [18] activities.…”

Crystal structure of 2-[(4-fluorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile, C16H16FN3OS

“…Nonnucleoside pyrimidine-based analogues have emerged as useful therapies against human immunode ciency viruses (HIV) [1][2][3][4], hepatitis B viruses (HBV) [5], herpes simplex viruses (HSV) [6,7], varicella-zoster virus (VZV) [8] and in uenza viruses [9]. A large number of pyrimidine-based antimetabolites are currently used as potent and selective anticancer activity [10][11][12].…”