1380109-82-9Relevant academic research and scientific papers
Discovery of efficacious pseudomonas aeruginosa-targeted siderophore-conjugated monocarbams by application of a semi-mechanistic pharmacokinetic/pharmacodynamic model
Murphy-Benenato, Kerry E.,Bhagunde, Pratik R.,Chen, April,Davis, Hajnalka E.,Durand-Réville, Thomas F.,Ehmann, David E.,Galullo, Vincent,Harris, Jennifer J.,Hatoum-Mokdad, Holia,Jahi?, Haris,Kim, Aryun,Manjunatha,Manyak, Erika L.,Mueller, John,Patey, Sara,Quiroga, Olga,Rooney, Michael,Sha, Li,Shapiro, Adam B.,Sylvester, Mark,Tan, Beesan,Tsai, Andy S.,Uria-Nickelsen, Maria,Wu, Ye,Zambrowski, Mark,Zhao, Shannon X.
supporting information, p. 2195 - 2205 (2015/03/30)
To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 μg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.
MONOBACTAMS
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Page/Page column 55, (2012/06/16)
The present invention is directed to a new class of monobactam derivatives and their use for treating bacterial infections.
