Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
Su
Dai-Shi
DS
Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, West Point, PA 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
Meiqing
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
Prasad
Sridhar
S
Yan
Youwei
Y
Perlow-Poehnelt
Rebecca
R
Torrent
Maricel
M
Miller
Mike
M
Vacca
Joe P
JP
Williams
Theresa M
TM
Anthony
Neville J
NJ
D000495:Allosteric Site; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008968:Molecular Conformation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D050505:Mutant Proteins; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase