Pharmacokinetics and Pharmacodynamics of Murepavadin in Neutropenic Mouse Models.

Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein-targeting antibiotics. It specifically interacts with LptD and inhibits lipopolysaccharide (LPS) transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa We determined the plasma protein binding and the pharmacokinetics of murepavadin in plasma and epithelial lining fluid (ELF; pulmonary) in infected animals, and we determined the exposure-response relationship. Treatment of CD-1 neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24 h, and the number of CFU per lung was determined. The sigmoid maximum-effect model was used to fit the dose-response, and the pharmacodynamic index (PDI) response was used to determine the PDI values, resulting in a static effect and 1-log kill reduction. Using R2 as an indicator of the best fit, the area under the concentration-time curve for the unbound fraction of the drug (fAUC)/MIC ratio correlated best with efficacy. The mean AUC required to provide a static effect was 36.83 mg h/liter (fAUC = 8.25 mg h/liter), and that to provide a 1-log reduction was 44.0 mg h/liter (fAUC = 9.86 mg h/liter). The mean static fAUC/MIC was determined to be 27.78, and that for a 1-log reduction was 39.85. These data may serve to determine doses in humans that are likely to be efficacious.

Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics.

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents.

Quantitative Determination of Resin Loading in Solid-Phase Organic Synthesis Using (13)C MAS NMR.

The use of quantitative carbon nuclear magnetic resonance spectroscopy ((13)C NMR) for the determination of resin loadings has been investigated. Magic angle spinning (MAS) NMR spectra have been obtained for solvent-swollen resins on a conventional 7 mm CP/MAS probe using the two pulse phase modulation (TPPM) proton decoupling sequence. Loadings of resin-bound organic compounds were evaluated via addition of tetrakis(trimethylsilyl)silane as reference or using the carbon resonances of the polymeric resin material as an internal standard. Results for several functionalized Wang and trityl resins are consistent with those obtained using well-established analytical methods. The (13)C NMR method has interesting applications in the field of solid-phase organic synthesis (SPOS), since no functional group acting as a support for the attachment of a quantifiable chromophore must be available in the material of interest.