Potent Inhibitors of LpxC for the Treatment of Gram-Negative Infections

• Published in: Journal of medicinal chemistry 2012-01, Vol.55 (2), p.914-923
• Main Authors: Brown, Matthew F, Reilly, Usa, Abramite, Joseph A, Arcari, Joel T, Oliver, Robert, Barham, Rose A, Che, Ye, Chen, Jinshan Michael, Collantes, Elizabeth M, Chung, Seung Won, Desbonnet, Charlene, Doty, Jonathan, Doroski, Matthew, Engtrakul, Juntyma J, Harris, Thomas M, Huband, Michael, Knafels, John D, Leach, Karen L, Liu, Shenping, Marfat, Anthony, Marra, Andrea, McElroy, Eric, Melnick, Michael, Menard, Carol A, Montgomery, Justin I, Mullins, Lisa, Noe, Mark. C, O’Donnell, John, Penzien, Joseph, Plummer, Mark S, Price, Loren M, Shanmugasundaram, Veerabahu, Thoma, Christy, Uccello, Daniel P, Warmus, Joseph S, Wishka, Donn G
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Catalytic Domain; Crystallography, X-Ray; Drug Resistance, Bacterial; Hydrogen Bonding; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Mice; Models, Molecular; Molecular Conformation; Phenyl Ethers - chemical synthesis; Phenyl Ethers - chemistry; Phenyl Ethers - pharmacology; Pseudomonas aeruginosa; Pseudomonas Infections - drug therapy; Rats; Stereoisomerism; Structure-Activity Relationship; Sulfides - chemical synthesis; Sulfides - chemistry; Sulfides - pharmacology; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2014748

In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid 1a.