ABSTRACT
E7090, a novel fibroblast growth factor receptors inhibitor, is currently under clinical development for the treatment of patients with solid tumors. The previous assay was insufficient in detection sensitivity for E7090 and high exposure of a dealkylated metabolite, M2, was noted in a clinical trial at low doses. Thus, a sensitive assay for the simultaneous determination of E7090 and M2 in human plasma has been developed using ultra-performance liquid chromatography with tandem mass spectrometer (UPLC-MS/MS). E7090 and M2 were extracted from 0.1 mL of plasma by protein precipitation and chromatographed on a reverse phase column utilizing at-column dilution which enables larger volume sample injection to the UPLC-MS/MS. E7090 and M2 were quantifiable from 0.025 ng/mL, which was 40-fold higher sensitivity than the previous assay. Accuracy as relative error and precision as relative standard deviation were within ± 15% and 15%, respectively, ensuring the reproducibility of the assay. The developed assay method was applied to a clinical trial of E7090, and plasma concentrations of E7090 and M2 were quantifiable up to 144 h postdose. These results indicated that the developed more sensitive assay was reproducible and was successfully applied to a clinical trial of E7090.
Subject(s)
Neoplasms , Receptors, Fibroblast Growth Factor , Humans , Chromatography, High Pressure Liquid/methods , Chromatography, Liquid/methods , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Fibroblast Growth Factor/therapeutic use , Reproducibility of Results , Tandem Mass Spectrometry/methods , Clinical Trials as TopicABSTRACT
The detection of thiol functionality and intramolecular disulfide bond formation of peptides using the α-Keggin type polyoxometalate molybdenum-oxygen cluster (H3PMo12O40·nH2O) is described. Our method entails the addition of this polyoxometalate to solutions of thiol, whereupon the color of the solution changes from colorless to deep blue. Reduction of the polyoxometalate from Mo(VI) to Mo(V) occurs with concomitant oxidation of the thiol functionality, to form disulfide bonds. To exemplify the utility this phenomenon, we accomplished the oxidation of glutathione, reduced linear oxytocin, bactenecin, and α-conotoxin SI; all of which proceeded smoothly and in good conversion in 24 h to less and were accomplished by a change in the color of the reaction solutions.
Subject(s)
Disulfides/chemistry , Sulfhydryl Compounds/analysis , Tungsten Compounds/chemistry , Molecular ConformationABSTRACT
Synthesis and evaluation of new scaffold phenylisoserine derivatives connected with the essential functional groups against SARS CoV 3CL protease are described. The phenylisoserine backbone was found by simulation on GOLD software and the structure activity relationship study of phenylisoserine derivatives gave SK80 with an IC50 value of 43µM against SARS CoV 3CL R188I mutant protease.
