Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptase

Pyridone inhibitors of non-nucleoside reverse transcriptase (NNRTI) with improved potency are reported. Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-12, Vol.21 (24), p.7344-7350
Main Authors: Gomez, Robert, Jolly, Samson, Williams, Theresa, Tucker, Thomas, Tynebor, Robert, Vacca, Joe, McGaughey, Georgia, Lai, Ming-Tain, Felock, Peter, Munshi, Vandna, DeStefano, Daniel, Touch, Sinoeun, Miller, Mike, Yan, Youwei, Sanchez, Rosa, Liang, Yuexia, Paton, Brenda, Wan, Bang-Lin, Anthony, Neville
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral activity
Antiviral agents
Binding Sites
Biological and medical sciences
Cell culture
Cell Line
Computer Simulation
Drug Design
Enzyme Activation - drug effects
Ethers
HIV
HIV - enzymology
HIV Reverse Transcriptase - antagonists & inhibitors
HIV Reverse Transcriptase - metabolism
Human immunodeficiency virus
Humans
Medical sciences
Non-nucleoside reverse transcriptase inhibitor
Pharmacology. Drug treatments
Protein Structure, Tertiary
Pyrazoles - chemistry
Pyridines - chemistry
Pyridinone
Pyridone
Pyridones - chemical synthesis
Pyridones - chemistry
Pyridones - pharmacology
Reverse Transcriptase Inhibitors - chemical synthesis
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - pharmacology
RNA-directed DNA polymerase
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Summary:Pyridone inhibitors of non-nucleoside reverse transcriptase (NNRTI) with improved potency are reported. Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 ( 1) and the more rigid indazole constraint of MK-6186 ( 2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI’s.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.10.027