Relationship between structure and bioavailability in a series of hydroxamate based metalloprotease inhibitors

Pharmacokinetic parameters for a series of C-terminally modified hydroxamate dipeptides were evaluated by in vitro and in vivo models. The presence of a tertiary base at the C-terminus significantly reduced biliary excretion and increased plasma half-life. Moreover, introduction of a thioether functionality produced a more favorable pharmacokinetic profile compared to the corresponding oxo- and aza-analogs.