Synthesis and hLDHA Inhibitory Activity of New Stiripentol-Related Compounds of Potential Use in Primary Hyperoxaluria

Human lactate dehydrogenase A (<i>h</i>LDHA) is a homotetrameric isozyme involved in the conversion of glyoxylate into oxalate in the cytosol of liver cells (hepatocytes) and partially responsible for the overproduction of oxalate in patients with the rare disease called primary hyperoxaluria (PH). Recently, <i>h</i>LDHA inhibition has been validated as a safe therapeutic method to try to control the PH disease. Stiripentol (STP) is an approved drug used in the treatment of seizures associated with Dravet's syndrome (a severe form of epilepsy in infancy) which, in addition, has been drawing interest in recent years also for potentially treating PH, due to its <i>h</i>LDHA inhibitory activity. In this work, several new STP-related compounds have been synthesized and their <i>h</i>LDHA inhibitory activity has been compared to that of STP. The synthesis of these analogues to STP was accomplished using crossed-aldol condensation guided by lithium enolate chemistry and a successive regioselective reduction of the resulting α,β-unsaturated ketones. The target molecules were obtained as racemates, which were separated into their enantiomers by chiral HPLC. The absolute configurations of pure enantiomers were determined by the modified Mosher's method and electronic circular dichroism (ECD) spectroscopy. For the inhibitory effect over the <i>h</i>LDHA catalytic activity, a kinetic spectrofluorometric assay was used. All the new synthesized compounds turned out to be more active at 500 μM (46-72% of inhibition percentage) than STP (10%), which opens a new line of study on the possible capacity of these analogues to reduce urinary oxalate levels in vivo more efficiently.