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: Dai-Shi Su, John J Lim, Elizabeth Tinney, Bang-Lin Wan, Mary Beth Young, Kenneth D Anderson, Deanne Rudd, Vandna Munshi, Carolyn Bahnck, Peter J Felock, Meiqing Lu, Ming-Tain Lai, Sinoeun Touch, Gregory Moyer, Daniel J Distefano, Jessica A Flynn, Yuexia Liang, Rosa Sanchez, Sridhar Prasad, Youwei Yan, Rebecca Perlow-Poehnelt, Maricel Torrent, Mike Miller, Joe P Vacca, Theresa M Williams, Neville J Anthony
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 17 Pg. 5119-23 (Sep 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19631528 (Publication Type: Journal Article)

Chemical References

• Anti-HIV Agents
• Mutant Proteins
• Quinolines
• Reverse Transcriptase Inhibitors
• Thiocarbamates
• reverse transcriptase, Human immunodeficiency virus 1
• HIV Reverse Transcriptase

Topics

• Allosteric Site
• Anti-HIV Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Crystallography, X-Ray
• HIV Reverse Transcriptase (antagonists & inhibitors, metabolism)
• Molecular Conformation
• Mutant Proteins (antagonists & inhibitors, metabolism)
• Quinolines (chemical synthesis, chemistry, pharmacology)
• Reverse Transcriptase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Thiocarbamates (chemistry, pharmacology)