Epimerization study of the L,L- and L,D-diastereoisomers of the calpain inhibitor MDL 28170 by capillary electrophoresis.

Abstract

MDL 28170, Cbz-(L)-Val-(D,L)-Phe-H, which exists as a mixture of L,L- and L,D-diastereoisomers, is a calpain inhibitor currently investigated as a novel therapeutic agent for the treatment of ischemic stroke and head and spinal trauma. This report describes a capillary electrophoresis (CE) method that uses sodium dodecyl sulfate (SDS) micellar electrokinetic conditions for the separation of the L,L- and L,D-diastereoisomers of MDL 28170. The report also describes the applications of this CE method to the study of epimerization of the L,L- and L,D-diastereoisomers in pH 7.4 phosphate buffered saline solution (PBS), rat and human plasma at 37 degrees C. The relative percent-time courses obtained showed interconversion of the diastereoisomers in all three matrices studied. However, the epimerization process in rat and human plasma was found to be at least 50 times faster than that in PBS. The epimerization half-life of the L,L-diastereoisomer in rat plasma was approximately 30 min, which is about three-fold faster than the observed elimination half-life of the L,L-diastereoisomer reported in a pharmacokinetic study following intravenous bolus dosing.

• Authors: Teng-Man Chen, Harlan K Jones
• Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences (J Chromatogr B Analyt Technol Biomed Life Sci) Vol. 809 Issue 1 Pg. 31-5 (Sep 25 2004) ISSN: 1570-0232 [Print] Netherlands
• PMID: 15282090 (Publication Type: Journal Article)

Chemical References

• Cysteine Proteinase Inhibitors
• Dipeptides
• Calpain
• calpain inhibitor III

Topics

• Animals
• Calpain (antagonists & inhibitors)
• Cysteine Proteinase Inhibitors (blood, chemistry)
• Dipeptides (blood, chemistry)
• Electrophoresis, Capillary (methods)
• Humans
• Rats
• Stereoisomerism