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 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.
Mordant
Céline
C
Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry Department, Campus de Maigremont BP315, F-27106 Val de Reuil Cedex, France.
Schmitt
Benoit
B
Pasquier
Elisabeth
E
Demestre
Christophe
C
Queguiner
Laurence
L
Masungi
Chantal
C
Peeters
Anik
A
Smeulders
Liesbeth
L
Bettens
Eva
E
Hertogs
Kurt
K
Heeres
Jan
J
Lewi
Paul
P
Guillemont
Jerome
J
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D000068696:Rilpivirine; D013056:Spectrophotometry, Ultraviolet
D009570:Nitriles; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine