Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

Primary
hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease
related to glyoxylate metabolism and characterized by accumulation
of calcium oxalate crystals. Current therapies involve hepatic and/or
renal transplantation, procedures that have significant morbidity
and mortality and require long-term immunosuppression. Thus, a pharmacological
treatment is urgently needed. We introduce here an unprecedented activity
of salicylic acid derivatives as agents capable of decreasing oxalate
output in hyperoxaluric hepatocytes at the low micromolar range, which
means a potential use in the treatment of PH1. Though correlation
of this phenotypic activity with glycolate oxidase (GO) inhibition
is still to be verified, most of the salicylic acids described here
are GO inhibitors with IC50 values down to 3 μM.
Binding mode of salicylic acids inside GO has been studied using in
silico methods, and preliminary structure–activity relationships
have been established. The drug-like structure and ease of synthesis
of our compounds make them promising hits for structural optimization.