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Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox

Authors :
Hermant, Paul
Bosc, Damien
Piveteau, Catherine
Gealageas, Ronan
Lam, BaoVy
Ronco, Cyril
Roignant, Matthieu
Tolojanahary, Hasina
Jean, Ludovic
Renard, Pierre-Yves
Lemdani, Mohamed
Bourotte, Marilyne
Herledan, Adrien
Bedart, Corentin
Biela, Alexandre
Leroux, Florence
Deprez, Benoit
Deprez-Poulain, Rebecca
Source :
Journal of Medicinal Chemistry; 20240101, Issue: Preprints
Publication Year :
2024

Abstract

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.

Details

Language :
English
ISSN :
00222623 and 15204804
Issue :
Preprints
Database :
Supplemental Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Periodical
Accession number :
ejs43403564
Full Text :
https://doi.org/10.1021/acs.jmedchem.7b01444