Because of the renal toxicity, and animal studies showing MKT077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P 1 site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P 1 site. Compounds with MICs of <4 g/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC 50 s) for Escherichia coli Ni-PDF were <0.1 M, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC 50 s of consistently >200 M for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzymeinhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.

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The U.S. Naval Research Laboratory has been engaged in a research program to develop sensor-based technologies to perform rapid automated fuel-quality surveillance. This approach is based on the development of quantitative models from the partial least-squares (PLS) regression of near-infrared (NIR) spectroscopic measurements of a representative calibration set of petroleum-derived fuels. As fuels from nonpetroleum sources become available it will be necessary to extend these chemometric models to accommodate Fischer-Tropsch (FT) synthetic fuels and biofuels. This extension is complicated by the fact that these new fuels will be initially introduced as blending components with petroleum-derived fuels. Chemometric modeling methodologies have been developed to identify and estimate the content of FT and biofuel present; then this information is used to estimate the bulk properties of the blends. With this approach, biodiesel content can be predicted, with respect to absolute error, to within 1.7% of its true value 95% of the time with a lower limit of detection of 1.5% using a single PLS model. The diesel fuel PLS property prediction models are applicable to diesel fuels blended with biodiesel fuel once that particular biodiesel fuel is incorporated in said models. The FT content in blends with petroleum fuels can be predicted, with respect to absolute error, to within 6.9% of its true value 95% of the time with a lower limit of detection of 15% using a series of paired PLS models for identification and quantification. In the presence of FT fuel, the PLS property models can be used after applying a correction factor that is derived from the identity and concentration of the FT fuel present.

Terbinafine-CYP2D6 inhibition was evaluated by assessing 48-hour concentration-time profiles of the tricyclic antidepressant desipramine in 12 healthy volunteers identified as extensive cytochrome P450 2D6 (CYP2D6) metabolizers by genotyping and phenotyping. Pharmacokinetics was evaluated at baseline (50 mg oral desipramine given alone), steady state (after 250 mg oral terbinafine for 21 days), and 2 and 4 weeks after terbinafine discontinuation. Pharmacodynamics was evaluated before and 2 hours after each desipramine administration, using Mini-Mental Status Examination (MMSE) and EGG. Terbinafine administration inhibited CYP2D6 metabolism, as indicated by the significant increase in desipramine C(max) (19 ng/ml vs. 36 ng/ml) and AUC0-infinity (482 ng.h/ml vs. 2383 ng.h/ml) and decrease in AUC0-24 and C(max) of the CYP2D6-mediated metabolite, 2-hydroxydesipramine. In addition, the C(max) and AGUC0-infinity of desipramine and metabolite were still elevated 4 weeks after terbinafine discontinuation. Caution should be exercised when coprescribing terbinafine and drugs metabolized by CYP2D6, particularly those with a narrow therapeutic index.

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Partial least-squares (PLS) was used to formulate property models for a set of 43 jet fuel samples using near-infrared (NIR), Raman, and gas chromatography (GC) data. A total of 28 different properties were evaluated for each technique. Given that the data set was small and several of the property distributions were nonideal, significance testing was used for model formulation and evaluation. A statistical F test was applied for selection of latent variables, determining the significance level of the model compared to random chance and evaluating the increase in prediction error when the expected sources of error were fully incorporated. A chart was used to categorize the confidence in the modeling ability as high, low, or indeterminate with the given data set.