The relationship between physicochemical properties, In vitro activity and pharmacokinetic profiles of analogues of diamine-Containing efflux pump inhibitors
| Autor: | Yakira Landaverry, Nicole Williams, Suzanne Chamberland, Thomas E. Renau, Vrushali Tembe, Deidre Madsen, Roger Leger, Rose Yen, Keith Huie, Michael N. Dudley, Jason Z. Zhang, David A. Griffith, Renee Litman, William J. Watkins |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Ofloxacin Clinical Biochemistry Biological Transport Active Pharmaceutical Science Microbial Sensitivity Tests Diamines Biochemistry Rats Sprague-Dawley Plasma Structure-Activity Relationship chemistry.chemical_compound Anti-Infective Agents Pharmacokinetics In vivo Drug Discovery Animals Structure–activity relationship Tissue Distribution Infusions Intravenous Molecular Biology Antibacterial agent Organic Chemistry Lipid Metabolism Acute toxicity Rats chemistry Pseudomonas aeruginosa Lipophilicity Molecular Medicine Efflux Lead compound Bacterial Outer Membrane Proteins |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 13:4241-4244 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2003.07.030 |
| Popis: | Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined. |
| Databáze: | OpenAIRE |
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