ABSTRACT
AIM: Perhexiline (PEX), being developed to treat hypertrophic cardiomyopathy, is toxic at levels above the therapeutic range. Plasma level monitoring is therefore essential. The absence of a UV-absorbing chromophore has in the past required quantitative analysis of PEX in plasma using lengthy derivatization methods, followed by HPLC and fluorescence detection. The routine and urgent analysis of a large number of patient plasma samples necessitates faster and reliable analytical methodology. RESULTS: An LC-MS/MS method, using two novel internal standards, has been validated for the quantitative measurement of PEX and its major hydroxy metabolites in human plasma. CONCLUSION: The assay has been applied to therapeutic drug monitoring (TDM), where PEX and the ratio of the drug to cis-hydroxy perhexiline, were measured at designated intervals.
Subject(s)
Blood Chemical Analysis/methods , Chromatography, High Pressure Liquid/methods , Drug Monitoring/methods , Perhexiline/blood , Perhexiline/metabolism , Tandem Mass Spectrometry/methods , Calibration , Humans , Quality ControlABSTRACT
We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).
