P793 Pharmacokinetic/pharmacodynamic modelling of the plasma bactericidal activity of NXL103 against Streptococcus pneumoniae and Staphylococcus aureus in phase I studies (original) (raw)

2007, International Journal of Antimicrobial Agents

ATPase activity of these enzymes. The objective of this work was to explore the structure activity relationships (SAR) of the series and to progress the compounds through preclinical development towards candidate nomination. Methods: The biochemical activity of compounds was determined using an in vitro ATPase assay. Minimal inhibitory concentrations (MIC) were determined using the CLSI broth microdilution method. Resistance frequency, time-kill and post-antibiotic effect were investigated using standard microbiological methods. The ADMET profile of various compounds was evaluated using in vitro methodology. Compounds from the series were evaluated in acute systemic infection models in mice. Results: A medicinal chemistry programme to explore the SAR of the compound series resulted in the synthesis of potent derivatives that have on-target activity against a range of species. Compounds within the series have nanomolar IC50s against gyrase and topo IV ATPase and singledigit, or better, microgram/mL MICs against S. aureus, E. faecalis, S. pneumoniae, M. catarrhalis and H. influenzae. The spontaneous resistance frequency observed for the series is low, consistent with dual targeting of DNA gyrase and topo IV. The compounds have a cidal mode of action with a time, but not concentration, dependant kill and no postantibiotic effect. The protein binding, cytotoxicity, chemical, plasma and microsomal stability, Caco-2 permeability, cytochrome P450 and hERG ion channel activities of the series have been explored. Selected derivatives have been characterised in vivo. The compounds were well tolerated and there was good bioavailability following IP or oral administration. Selected compounds demonstrated efficacy in murine septicaemia models of staphylococcal infection. Conclusion: The properties of the inhibitors are consistent with a compound series capable of optimisation into an antibiotic targeting both respiratory tract and drug-resistant Gram-positive infections.

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