title: 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 solution. In the context of drug development, this study reveals that cyanothiazolidine moieties are problematic due to their rapid P450-mediated oxidation and the unpredictable stability of the corresponding metabolites.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, QC, H3A 0B8 (Canada).
authors.forename: Paolo
authors.initials: P
authors.lastname: Schiavini
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, QC, H3A 0B8 (Canada).
authors.forename: Joshua
authors.initials: J
authors.lastname: Pottel
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, QC, H3A 0B8 (Canada). k.auclair@mcgill.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, QC, H3A 0B8 (Canada). nicolas.moitessier@mcgill.ca.
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
mesh_terms: D002626:Chemistry, Pharmaceutical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism*; D053778:Thiazolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D053778:Thiazolidines; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
keywords: cyanothiazolidines; cytochrome P450s; epimerization; metabolism; sulfur oxidation