1. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate.
- Author
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Yoshida K, Nakayama K, Ohtsuka M, Kuru N, Yokomizo Y, Sakamoto A, Takemura M, Hoshino K, Kanda H, Nitanai H, Namba K, Yoshida K, Imamura Y, Zhang JZ, Lee VJ, and Watkins WJ
- Subjects
- Animals, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents chemistry, Drug Evaluation, Preclinical, Drug-Related Side Effects and Adverse Reactions, Female, Haplorhini, Infusions, Intravenous, Male, Membrane Transport Proteins, Microbial Sensitivity Tests, Molecular Structure, Piperidines chemical synthesis, Piperidines chemistry, Quaternary Ammonium Compounds administration & dosage, Quaternary Ammonium Compounds chemical synthesis, Quaternary Ammonium Compounds chemistry, Rats, Rats, Sprague-Dawley, Solubility, Stereoisomerism, Anti-Bacterial Agents pharmacology, Bacterial Outer Membrane Proteins antagonists & inhibitors, Piperidines pharmacology, Pseudomonas Infections drug therapy, Pseudomonas aeruginosa drug effects, Quaternary Ammonium Compounds pharmacology
- Abstract
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.
- Published
- 2007
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