Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox

Hydroxamic
acids are outstanding zinc chelating groups that can
be used to design potent and selective metalloenzyme inhibitors in
various therapeutic areas. Some hydroxamic acids display a high plasma
clearance resulting in poor in vivo activity, though they may be very
potent compounds in vitro. We designed a 57-member library of hydroxamic
acids to explore the structure–plasma stability relationships
in these series and to identify which enzyme(s) and which pharmacophores
are critical for plasma stability. Arylesterases and carboxylesterases
were identified as the main metabolic enzymes for hydroxamic acids.
Finally, we suggest structural features to be introduced or removed
to improve stability. This work thus provides the first medicinal
chemistry toolbox (experimental procedures and structural guidance)
to assess and control the plasma stability of hydroxamic acids and
realize their full potential as in vivo pharmacological probes and
therapeutic agents. This study is particularly relevant to preclinical
development as it allows obtaining compounds equally stable in human
and rodent models.