Abstract
DA-7010 is a new candidate for an antibacterial agent that targets Gram-negative pathogens by acting as a leucyl-tRNA synthetase inhibitor. In this study, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine DA-7010 levels in the plasma from mice, rats, and dogs. Plasma samples were mixed with methanol for protein precipitation. Chromatographic separation was carried out using a reversed-phase C18 column (Agilent Poroshell 120, 50 × 3.0 mm, 2.7 μm). An isocratic elution of the mobile phase consisting of 5 mM formic acid in water and acetonitrile at a ratio of 84:16 (v/v) was applied at a flow rate of 0.3 mL/min. The total chromatographic run time was 3.5 min. Multiple reaction monitoring (MRM) mode was used for mass spectrometric detection using an Agilent 6460 triple quadrupole coupled with an electrospray ionization (ESI) source operated in positive-ion mode. The MRM transitions analyzed were m/z 220.1→162.1 for DA-7010 and m/z 206.1→170.1 for the internal standard (structural analogue of DA-7010). Calibration curves were constructed in the range of 10–10,000 ng/mL. The intra- and interday precision and accuracy were within 11.3%, excluding those for the lower limit of quantification (LLOQ) samples, which were within 17.1%. The developed LC-MS/MS method was successfully validated and applied in preclinical pharmacokinetic studies of DA-7010 in mice, rats, and dogs following single oral administrations. The oral absorption of DA-7010 was rapid, and the systemic exposure was approximately four times higher in the dogs than in the mice or rats.
Highlights
Infections of carbapenem-resistant or multidrug-resistant Gram-negative pathogens are major healthcare concerns due to high morbidity and the absence of new drug development [1]
Method and effective oral doses of 1.9–3 mg/kg that protected 50% of mice systemically infected with carbapenem-resistant Acinetobacter bauWe optimized the instrumental parameters for mass spectrometry to obtain sensitive mannii (ED50 ) [2,3]
89.8–106%, including for the lower limit of quantification (LLOQ). These results demonstrate that the developed method had sufficient precision and accuracy for the quantification of DA-7010 in plasma from mice, rats, and dogs
Summary
Infections of carbapenem-resistant or multidrug-resistant Gram-negative pathogens are major healthcare concerns due to high morbidity and the absence of new drug development [1]. DA-7010 (((2S,7R)-7-methyl-7,8-dihydro-2H-1,6,9-trioxa-9a-borabenzo[cd]azulen2-yl)methanamine; Figure 1a; confirmed by HR-MS and 1 H-NMR spectra (Figure S1)) is a new candidate for an antibacterial agent against Gram-negative pathogens due to acting as a leucyl-tRNA synthetase (LeuRS) inhibitor with a tricyclic benzoxaborole moiety [2,3]. Benzoxaborole moieties have been applied in the design of various compounds for antimicrobial and anti-inflammatory agents due to their drugability [4]. Because the structures of aminoacyl-tRNA synthetases (ARSs) found in eukaryotes have considerable structural differences from those in prokaryotes, it is possible to develop highly selective inhibitors that can achieve antibacterial-specific responses [6]. Basic and clinical studies have been underway to apply
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