Evolution of Anti-HIV Drug CandidatesPart 2: Diaryltriazine (DATA) Analogues

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

doi:10.1016/s0960-894x(01)00411-5

Cited by 118 publications

(61 citation statements)

References 6 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: 79%

“…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: 79%

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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“…Thus α-anilinophenylacetamide (α-APA) was identified as the next (potential) anti-HIV drug candidate (129). As α-APA (loviride) did not fulfill the desired pharmacokinetic requirements (part of the problem was that loviride, given its chiral structure, actually forms a racemic mixture), new derivatives were synthesized, e.g., iminothiourea (ITU) (130), diaryltriazine (DATA) (131), and diarylpyrimidine (DAPY) analogs (132). The DAPY family yielded three congeners: dapivirine (TMC120), still under development as a topical microbicide to prevent HIV infections; etravirine (TMC125) (133), which has been licensed (Intelence R ); and rilpivirine (R278474, TMC278) (134), which can be considered Dr. Paul Janssen's final legacy.…”

Section: Wwwannualreviewsorg • Selective Antiviral Chemotherapymentioning

confidence: 99%

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

Clercq

2011

Annu. Rev. Pharmacol. Toxicol.

148

144

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My search for a selective antiviral chemotherapy started more than 40 years ago with interferon inducers, then shifted to nucleoside analogs with the discovery of BVDU (brivudin), a highly selective anti-HSV-1 and anti-VZV agent, and to dideoxynucleoside analogs such as d4T (stavudine), anti-HIV agents. The search culminated in the discovery of acyclic nucleoside phosphonates (ANPs) (in collaboration with Antonin Holý), a key class of compounds active against HIV, hepatitis B virus, and DNA viruses at large; the best known of these compounds is tenofovir. Along the way, the principle of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was established. This work, initiated in collaboration with the late Paul A.J. Janssen, eventually led to the identification of rilpivirine as perhaps an "ideal" NNRTI.1

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“…A second step was to include assessment of metabolic stability early in the discovery process, thereby establishing a structure-metabolism relationship. One of the early lead compounds was indeed prone to metabolism (22), leading to a short half-life in plasma when tested in vivo. The combination of structureactivity relationship and structure-metabolism relationship allowed concurrent optimization of structures for broadspectrum anti-HIV activity and metabolic stability.…”

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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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310

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 CandidatesPart 2: Diaryltriazine (DATA) Analogues

Cited by 118 publications

References 6 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

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

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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