Design of new human Dihydroorotate Dehydrogenase inhibitors: amide bioisosterism in MEDS433 optimization

Human Dihydroorotate Dehydrogenase (hDHODH) catalyzes the stereoselective oxidation of L- dihydroorotate (DHO) to orotate (ORO) in the de novo pyrimidine biosynthesis. Recent studies proved that inhibiting hDHODH constitutes a promising pharmacological strategy for treatment of hematological malignancies, such as acute myeloid leukemia (AML)1,2, and viral pathologies3. During the last few years, MEDSynth research group designed a first generation of inhibitors based on a hydroxypyrazolo[1,5-a]pyridine scaffold, working as unusual carboxylic acid bioisostere, joined to either a biphenyl or a diaryl ether moiety via an amide linker. Within the series, MEDS433 was the most promising compound: hence, it displayed a high in vitro inhibitory activity (IC50 = 1.2 nM), comparable to that of Brequinar (IC50 = 1.8 nM) in the enzymatic assay.4 Despite its high potency, this lead compound suffers from poor solubility and optimization of its drug-like properties is necessary in order to perform further pre-clinical studies. In this work, aiming to improve the solubility without losing in binding affinity for the protein, a new analogues series was developed by bioisosterically replacing the amide linker. Inspired by promising results in literature studies5, several amide non-classical bioisosteres, such as triazoles, oxadiazole and diazo- moieties were embedded in MEDS433 as potential new linkers (Figure 1). Theoretical design, synthesis and enzymatic assay are here presented and discussed.