Modulazione isosterica del gruppo ammidico in MEDS433 nella progettazione di inibitori dell'hDHODH

Human dihydroorotate dehydrogenase (hDHODH) is a ubiquitous flavoprotein that catalyzes the fourth step of de novo pyrimidine biosynthesis. Recent studies have identified hDHODH as a promising pharmacological target for treating hematological malignancies and viral infections. The MEDSynth research group has developed hDHODH inhibitors, characterized by an acidic hydroxypyrazole[1,5-a]pyridine scaffold linked to a lipophilic tetrafluorobiphenyl substituent via an amide linker. Among these inhibitors, MEDS433 emerged as the most promising compound, demonstrating high in vitro inhibitory activity in enzymatic assays (IC50 = 1.2 nM), comparable to the phase II clinical candidate Brequinar (IC50 = 1.8 nM). Despite its potency and selectivity, MEDS433 presented poor solubility, requiring improvements to advance as a potential drug candidate for further clinical trials. In this Master Thesis, a new series of analogs through isosteric substitution of the amide linker in MEDS433 was designed. Specifically, we replaced the amide group with some isosteres such us sulfonamide, reverse sulfonamide, reverse amide, alkene, and amidine. These modifications aimed to investigate the role of amide as a pharmacophore and elucidate its role in the solubility and metabolic stability of the original lead compound. 

Here we present and discuss the new analogs’ theoretical design, synthesis, and enzymatic assay results.