Development of Potent Human Dihydroorotate Dehydrogenase Inhibitors Able to Induces Myeloid Differentiation

The success of brequinar, one of the most potent human dihydroorotate dehydrogenase (hDHODH) inhibitors, to induce in vitro and in vivo differentiation in mouse acute myeloid leukaemia (AML)[1] models, encourages researches to design new hDHODH inhibitors. By applying innovative scaffold-hopping replacement to brequinar, we designed a first generation of hDHODH inhibitors presenting nM activity on the isolated hDHODH.[2] In this occasion, we are presenting a second generation able to reach the brequinar hDHODH potency. Compound 1 was found also able to restore the myeloid differentiation in leukaemia cell lines at concentrations one digit lower than brequinar. Theoretical design, modelling, synthesis, SAR, X-ray crystallographic data, biological assays, preliminary ADME and in vivo toxicity are here presented and discussed.