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Journal Articles Journal of Medicinal Chemistry Year : 2017

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 identify both 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 provides thus 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 to obtain compounds equally stable in human and rodent models.
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hal-03054238 , version 1 (11-12-2020)



Paul Hermant, Damien Bosc, Catherine Piveteau, Ronan Gealageas, Baovy Lam, et al.. Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox. Journal of Medicinal Chemistry, 2017, 60 (21), pp.9067-9089. ⟨10.1021/acs.jmedchem.7b01444⟩. ⟨hal-03054238⟩
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