Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains

Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interest...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2007-05, Vol.42 (5), p.567-579
Main Authors: Mordant, Céline, Schmitt, Benoit, Pasquier, Elisabeth, Demestre, Christophe, Queguiner, Laurence, Masungi, Chantal, Peeters, Anik, Smeulders, Liesbeth, Bettens, Eva, Hertogs, Kurt, Heeres, Jan, Lewi, Paul, Guillemont, Jerome
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Chromatography, High Pressure Liquid
Diarylpyrimidine (DAPY)
Dogs
Female
HIV-1
HIV-1 - drug effects
Magnetic Resonance Spectroscopy
Male
Mass Spectrometry
Medical sciences
Nitriles - chemical synthesis
Nitriles - pharmacology
NNRTI
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
Rats, Wistar
Reverse Transcriptase Inhibitors - chemical synthesis
Reverse Transcriptase Inhibitors - pharmacology
Rilpivirine
Spectrophotometry, Ultraviolet
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Summary:Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials. [Display omitted] Design and synthesis of TMC278 analogues by modulation on the left wing of the diarylpyrimidine (DAPY) were investigated.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2006.11.014