Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1

Guillemont, Jérôme; Pasquier, Elisabeth; Palandjian, Patrice; Vernier, Daniel; Gaurrand, Sandrine; Lewi, Paul; Heeres, Jan; Jonge, Marc R. de; Koymans, Lucien M. H.; Daeyaert, Frits; Vinkers, Maarten; Arnold, Eddy; Das, Kalyan; Pauwels, Rudi; Andries, Koen; Béthune, Marie‐Pierre de; Bettens, Eva; Hertogs, Kurt; Wigerinck, Piet; Timmerman, Philip; Janßen, Paul

doi:10.1021/jm040838n

Cited by 116 publications

(75 citation statements)

References 16 publications

(33 reference statements)

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“…[18,19] With the aim to optimize DAPY compounds, rilpivirine (RPV) was designed with the focus of establishing interactions with the conserved amino acids in the NNRTI binding pocket, in particular W229. [20] In vitro, RPV shows a resistance profile and genetic barrier to the development of resistance comparable to those of ETR. [21] High-resolution crystal structures of RPV in complex with L100I/K103N HIV-1 RT show the inhibitor reaching deeper into the NNRTI binding pocket toward amino acid W229 compared with ETR.…”

Section: Introductionmentioning

confidence: 99%

Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

et al. 2011

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An integrated computational and statistical approach was used to determine the association of non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, efavirenz and etravirine with resistance mutations that cause therapeutic failure and their impact on NNRTI resistance. Mutations detected for nevirapine virological failure with a prevalence greater than 10% in the used patient set were: K103N, Y181C, G190A, and K101E. A support vector regression model, based on matched genotypic/phenotypic data (n=850), showed that among 6365 analyzed mutations, K103N, Y181C and G190A have the first, third, and sixth greatest significance for nevirapine resistance, respectively. The most common indicator of treatment failure for efavirenz was K103N mutation present in 56.7% of the patients where the drug failed, followed by V108I, L100I, and G190A. For efavirenz resistance, K103N, G190, and L100I have the first, fourth, and eighth greatest significance, respectively, as determined in support vector regression model. No positive interactions were observed among nevirapine resistance mutations, while a more complex situation was observed with treatment failure of efavirenz and etravirine, characterized by the accumulation of multiple mutations. Docking simulations and free energy analysis based on docking scores of mutated human immunodeficiency virus (HIV) RT complexes were used to evaluate the influence of selected mutations on drug recognition. Results from support vector regression were confirmed by docking analysis. In particular, for nevirapine and efavirenz, a single mutation K103N was associated with the most unfavorable energetic profile compared to the wild-type sequence. This is in line with recent clinical data reporting that diarylpyrimidine etravirine, a very potent third generation drug effective against a wide range of drug-resistant HIV-1 variants, shows increased affinity towards K103N/S mutants due to its high conformational flexibility.

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Section: Introductionmentioning

confidence: 99%

Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

et al. 2011

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“…There is an overwhelming evidence indicating that various heterocyclic cores attached to a diaryl system possess diverse pharmacological activities viz., COX II inhibition [4], allosteric modulation of GABA A receptor [5] and estrogen receptor [6], adenosine receptor antagonism [7], selective p38a inhibition [8], cannabinoid receptor antagonism [9], antimitotic activity [10] (combretastatin analogs), antiplatelet activity [11] and anti-HIV-1 activity [12] (TMC-125).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

Ramajayam

Giridhar

Yadav

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.

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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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Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1

Cited by 116 publications

References 16 publications

Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

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

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