Open AccessDual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria
Author(s) -
J. Ding,
R. Gumpena,
Marc-Olivier Boily,
Alexandre Caron,
Oliver Chong,
Jennifer H. Cox,
Valérie Dumais,
Samuel Gaudreault,
Aaron H. Graff,
Andrew G. King,
John Knight,
Renata M. Oballa,
Jayakumar Surendradoss,
Tim Y. Tang,
Joyce Wu,
W. Todd Lowther,
David A. Powell
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00196
Subject(s) - in vivo , lactate dehydrogenase , oxalate , chemistry , primary hyperoxaluria , pharmacology , biochemistry , enzyme , medicine , biology , microbiology and biotechnology , organic chemistry
Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC 50 of 88 nM for oxalate reduction in an Agxt -knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.