title: Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, West Point, PA 19486, USA. Dai-Shi.X.Su@gsk.com
authors.forename: Dai-Shi
authors.initials: DS
authors.lastname: Su
authors.forename: John J
authors.initials: JJ
authors.lastname: Lim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tinney
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Anderson
authors.forename: Deanne
authors.initials: D
authors.lastname: Rudd
authors.forename: Vandna
authors.initials: V
authors.lastname: Munshi
authors.forename: Carolyn
authors.initials: C
authors.lastname: Bahnck
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Meiqing
authors.initials: M
authors.lastname: Lu
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Sinoeun
authors.initials: S
authors.lastname: Touch
authors.forename: Gregory
authors.initials: G
authors.lastname: Moyer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Distefano
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Flynn
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Liang
authors.forename: Rosa
authors.initials: R
authors.lastname: Sanchez
authors.forename: Sridhar
authors.initials: S
authors.lastname: Prasad
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Perlow-Poehnelt
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Mike
authors.initials: M
authors.lastname: Miller
authors.forename: Joe P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: Neville J
authors.initials: NJ
authors.lastname: Anthony
mesh_terms: 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
chemical_list: 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