Metabolic Instability of Cyanothiazolidine-Based Prolyl Oligopeptidase Inhibitors: a Structural Assignment Challenge and Potential Medicinal Chemistry Implications.

ABSTRACT: As part of the development of cyanothiazolidine-based prolyl oligopeptidase inhibitors, initial metabolism studies suggested multiple sites of oxidation by P450 enzymes. Surprisingly, in-depth investigations revealed that epimerization at multiple stereogenic centers was responsible for the conversion of the single primary metabolite into a panel of secondary metabolites. The rapid isomerization of all seven detected molecules precluded the use of NMR spectroscopy or X-ray crystallography for complete structural determination, presenting an interesting structure elucidation challenge. Through a combination of LC-MS analysis, synthetic work, deuterium exchange studies, and computational predictions, we were able to characterize all metabolites and to elucidate their dynamic behavior in solu

SUBMITTER: Schiavini P 

PROVIDER: S-EPMC5177022 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature