Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif.
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
Su
Dai-Shi
DS
Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, West Point, PA 19486, USA.
Lim
John J
JJ
Tinney
Elizabeth
E
Tucker
Thomas J
TJ
Saggar
Sandeep
S
Sisko
John T
JT
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
D000494:Allosteric Regulation; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D004987:Ethers; D011720:Pyrazoles; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; C118531:pyrazolopyridine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase