Six esterase inhibitors, namely EDTA·2Na(+), NaF, phenylmethanesulfonyl fluoride, dichlorvos, bis-nitrophenyl phosphate (BNPP) and thenoyltrifluoroacetone, and the mixture of NaF and BNPP, were evaluated for the stabilization of labile benzoate containing zeylenone in rat plasma. The mixture appeared to exhibit the most effectively stabilizing effect with the degraded content of zeylenone decreasing from >60% (in the absence of inhibitors) to <6%. Following the stabilization by the addition of NaF (5 mM) and BNPP (5 mM), the analytes in rat plasma were acidified by formic acid and extracted into ethyl acetate at 0°C. After chromatographic separation, the detection of zeylenone was performed on a 3200 Q-Trap with positive ion electrospray mode, monitoring the ion transition m/z 383.2 → 105.0. The method was validated over the range from 2.68 to 1340 ng/mL with inter- and intra-run precision for the quality control samples being less than 6.8%. The assay accuracy was within 100 ± 7.0%. The validated method was successfully applied to a pharmacokinetic study in rats after the intratracheal administration of zeylenone in free drug or polymeric micellar solutions. The results showed that the pulmonary absorption of zeylenone loaded in micelles was significantly retarded compared with that of free drug solutions.
Background:
Protein tyrosine phosphatases 1B are considered to be a desirable validated
target for therapeutic development of type II diabetes and obesity.
Methods:
A new series of imidazolyl flavonoids as potential protein tyrosine phosphatase inhibitors
were synthesized and evaluated.
Results:
Bioactive results indicated that some synthesized compounds exhibited potent protein
phosphatase 1B (PTP1B) inhibitory activities at the micromolar range. Especially, compound 8b
showed the best inhibitory activity (IC50=1.0 µM) with 15-fold selectivity for PTP1B over the
closely related T-cell protein tyrosine phosphatase (TCPTP). Cell viability assays indicated that 8b
is cell permeable with lower cytotoxicity. Molecular modeling and dynamics studies revealed the
reason for selectivity of PTP1B over TCPTP. Quantum chemical studies were carried out on these
compounds to understand the structural features essential for activity.
Conclusion:
Compound 8b should be a potential selective PTP1B inhibitor.
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