Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses.
Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.
Su
Dai-Shi
DS
Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, P.O. Box 4, West Point, Pennsylvania 19486, USA. Dai-Shi.X.Su@gsk.com
Lim
John J
JJ
Tinney
Elizabeth
E
Wan
Bang-Lin
BL
Young
Mary Beth
MB
Anderson
Kenneth D
KD
Rudd
Deanne
D
Munshi
Vandna
V
Bahnck
Carolyn
C
Felock
Peter J
PJ
Lu
Meiquing
M
Lai
Ming-Tain
MT
Touch
Sinoeun
S
Moyer
Gregory
G
DiStefano
Daniel J
DJ
Flynn
Jessica A
JA
Liang
Yuexia
Y
Sanchez
Rosa
R
Perlow-Poehnelt
Rebecca
R
Miller
Mike
M
Vacca
Joe P
JP
Williams
Theresa M
TM
Anthony
Neville J
NJ
D000818:Animals; D002460:Cell Line; D004285:Dogs; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004987:Ethers; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase