Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate seri...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-02, Vol.55 (4), p.1662-1670
Main Authors: Montgomery, Justin I, Brown, Matthew F, Reilly, Usa, Price, Loren M, Abramite, Joseph A, Arcari, Joel, Barham, Rose, Che, Ye, Chen, Jinshan Michael, Chung, Seung Won, Collantes, Elizabeth M, Desbonnet, Charlene, Doroski, Matthew, Doty, Jonathan, Engtrakul, Juntyma J, Harris, Thomas M, Huband, Michael, Knafels, John D, Leach, Karen L, Liu, Shenping, Marfat, Anthony, McAllister, Laura, McElroy, Eric, Menard, Carol A, Mitton-Fry, Mark, Mullins, Lisa, Noe, Mark C, O’Donnell, John, Oliver, Robert, Penzien, Joseph, Plummer, Mark, Shanmugasundaram, Veerabahu, Thoma, Christy, Tomaras, Andrew P, Uccello, Daniel P, Vaz, Alfin, Wishka, Donn G
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Amidohydrolases - antagonists & inhibitors
Animals
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - pharmacology
ANTIMICROBIAL AGENTS
BACTERIA
BASIC BIOLOGICAL SCIENCES
Crystallography, X-Ray
Gram-Negative Bacteria - drug effects
Gram-Negative Bacterial Infections - drug therapy
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - pharmacokinetics
Hydroxamic Acids - pharmacology
INHIBITION
INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Protein Conformation
Pseudomonas aeruginosa - drug effects
Pseudomonas aeruginosa - enzymology
Pyridones - chemical synthesis
Pyridones - pharmacokinetics
Pyridones - pharmacology
Rats
SOLUBILITY
Stereoisomerism
Structure-Activity Relationship
Sulfonic Acids - chemical synthesis
Sulfonic Acids - pharmacokinetics
Sulfonic Acids - pharmacology
SYNTHESIS
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Summary:The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm2014875