Evolution of anti-HIV drug candidates. Part 3: diarylpyrimidine (DAPY) analogues

Ludovici, Donald; Corte, Bart L. De; Kukla, Michael J.; Ye, Hong; Ho, Ching‐Yin; Lichtenstein, Mark A.; Kavash, Robert W.; Andries, Koen; Béthune, M.-P. De; Azijn, Hilde; Pauwels, Rudi; Lewi, Paul; Heeres, Jan; Koymans, Lucien M. H.; Jonge, Marc R. de; Aken, Koen Van; Daeyaert, Frits; Das, Kalyan; Arnold, Edward; Janßen, Paul

doi:10.1016/s0960-894x(01)00412-7

Cited by 187 publications

(104 citation statements)

References 15 publications

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“…Although the relatively rapid selection of drug-resistant viruses is clearly the Achilles' heel of most NN-RTIs, the DATA and DAPY compounds included in the present study proved to be highly effective in vitro against wild-type and various singleand double-mutant strains of HIV-1 (11,12). The DAPY compounds R147681 (TMC-120) and R165335 (TMC-125) and the DATA compound R152649 have previously been evaluated against NN-RTI-resistant HIV variants encoding L100I, K103N, Y181C, Y188L, and G190A/S mutations, with resulting EC 50 In conclusion, the DATA and DAPY compounds described here constitute a new series of NN-RTIs that are more potent than earlier RTIs and have a favorable TI.…”

Section: Vol 48 2004 Data and Dapy Compounds As Potent Nn-rti Micromentioning

confidence: 80%

“…The search for new antiretrovirals led to the discovery of new families of NN-RTIs, the DATA and DAPY compounds (11,12). Since these DATA and DAPY compounds showed high potency in a MT-4 cell-based assay, we decided to further explore the antiviral and immunosuppressive activity of these compounds in our physiologically relevant in vitro model of MO-DC/CD4…”

Section: Discussionmentioning

confidence: 99%

“…Multidisciplinary research recently led to the discovery of a series of diaryltriazines (DATAs) and diarylpyrimidines (DAPYs) that are extremely potent against wild-type and various mutant strains of HIV type 1 (HIV-1), as evaluated in cytopathicity protection assays with the MT-4 T-cell line (11,12).…”

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confidence: 99%

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A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides

Herrewege¹,

Vanham

Michiels³

et al. 2004

Antimicrob Agents Chemother

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An in vitro model of monocyte-derived dendritic cells (MO-DC) and CD4؉ T cells, representing the primary targets of sexual human immunodeficiency virus (HIV) transmission, was used to evaluate the antiviral and immune suppressive activity of new classes of nonnucleoside reverse transcriptase inhibitors, diaryltriazines (DATAs) and diarylpyrimidines (DAPYs), compared to the reference compounds UC-781 and PMPA. Antiviral activity (as reflected by the 50% effective concentration [EC 50 ]) was determined by treating HIV-infected MO-DC/CD4؉ -T-cell cocultures with a dose range of a compound during 14 days, followed by analysis of supernatants in HIV p24 antigen enzyme-linked immunosorbent assay. A limited, 24-h treatment evaluated the compounds as microbicides. Viral rescue was evaluated in a PCR by monitoring proviral DNA in secondary cultures with phytohemagglutinin-interleukin-2 blasts. We determined 50% immunosuppressive concentrations in mixed leukocyte cultures of MO-DC and allogeneic T cells, with compound either continuously present or present only during the first 24 h. The EC 50 values of DATA and DAPY compounds ranged from 0.05 to 3 nM compared to 50 nM for UC-781 and 89 nM for PMPA. When evaluated in the "microbicide" setting, the most potent compounds completely blocked HIV infection at 10 to 100 nM. The immunosuppressive concentrations were well above the EC 50 , resulting in favorable therapeutic indices for all compounds tested. The DATA and DAPY compounds described here are more potent than earlier reverse transcriptase inhibitors and show favorable pharmacological profiles in vitro. They could strengthen the antiretroviral armamentarium and might be useful as microbicides.

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Section: Vol 48 2004 Data and Dapy Compounds As Potent Nn-rti Micromentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides

Herrewege¹,

Vanham

Michiels³

et al. 2004

Antimicrob Agents Chemother

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“…Because toxicity and drug resistance complicate treatment strategies, the development of new anti-AIDS drugs remains essential. (1,2), also referred to as rilpivirine and R278474, is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that was developed in a multidisciplinary structure-based design effort (3,4) intended to discover drugs that can inhibit a wide range of the known drug-resistant HIV-1 strains. In cell-based assays, TMC278 inhibits a broad spectrum of HIV-1 variants (Table 1), including strains that are partially or completely resistant to the existing NNRTI drugs (3).…”

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confidence: 99%

High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations

Das

Bauman

Clark

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that is highly effective in treating wild-type and drug-resistant HIV-1 infections in clinical trials at relatively low doses (ϳ25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 Å resolution, using an RT crystal form engineered by systematic RT mutagenesis. This highresolution structure reveals that the cyanovinyl group of TMC278 is positioned in a hydrophobic tunnel connecting the NNRTI-binding pocket to the nucleic acid-binding cleft. The crystal structures of TMC278 in complexes with the double mutant K103N/Y181C (2.1 Å) and L100I/K103N HIV-1 RTs (2.9 Å) demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/TMC278 structure, loss of the aromatic ring interaction caused by the Y181C mutation is counterbalanced by interactions between the cyanovinyl group of TMC278 and the aromatic side chain of Y183, which is facilitated by an ϳ1.5 Å shift of the conserved Y183MDD motif. In the L100I/K103N RT/ TMC278 structure, the binding mode of TMC278 is significantly altered so that the drug conforms to changes in the binding pocket primarily caused by the L100I mutation. The flexible binding pocket acts as a molecular ''shrink wrap'' that makes a shape complementary to the optimized TMC278 in wild-type and drug-resistant forms of HIV-1 RT. The crystal structures provide a better understanding of how the flexibility of an inhibitor can compensate for drug-resistance mutations.drug design ͉ drug resistance ͉ nonnucleoside reverse transcriptase inhibitor ͉ polymerase ͉ x-ray crystallography C ombinations of drugs have been used to successfully treat HIV-1 infections, permitting dramatic reduction in viral loads and restoration of the immune system. However, drug treatments do not eliminate the infection and treatment must be life-long. There are problems with drug toxicity, and prolonged drug exposure can lead to the emergence of drug-resistant mutant viruses. Because toxicity and drug resistance complicate treatment strategies, the development of new anti-AIDS drugs remains essential., also referred to as rilpivirine and R278474, is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that was developed in a multidisciplinary structure-based design effort (3, 4) intended to discover drugs that can inhibit a wide range of the known drug-resistant HIV-1 strains. In cell-based assays, TMC278 inhibits a broad spectrum of HIV-1 variants (Table 1), including strains that are partially or completely resistant to the existing NNRTI drugs (3). Phase I and II clinical trials have shown that TMC278 effectively reduces viral load and maintains low viral load levels with no virus rebound in patients even after 48 weeks of treatment (5, 6).Crystal structures of HIV-1 RT/NNRTI complexes were solved in the course of developing TMC278 (7, 8) along a path that originated with the first-generation TIBO compounds (9). Most of those structures were obtained at ϳ...

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“…Our strategy ensured a data-driven and rapid selection process that, along with structural insights, paved the road for the discovery of the imidoyl thiourea (ITU), diaryltriazines (DATA), and the diarylpyrimidine (DAPY) series (21)(22)(23)). Here we report the pharmacological characteristics of TMC125 (also known as R165335) (Fig.…”

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confidence: 99%

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

Andries¹,

Azijn

Thielemans³

et al. 2004

Antimicrob Agents Chemother

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258

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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...

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Evolution of anti-HIV drug candidates. Part 3: diarylpyrimidine (DAPY) analogues

Cited by 187 publications

References 15 publications

A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides

A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides

High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations

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

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