PROCEEDINGS OF THE MERCK & ELSEVIER YOUNG CHEMISTSSYMPOSIUM

The success of brequinar, one of the most potent human dihydroorotate dehydrogenase (hDHODH) inhibitors, able to induce in vitro and in vivo myeloid differentiation in mouse acute myeloid leukaemia (AML) models [1], 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 [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 two leukaemia cell lines (U937 and THP-1) at concentrations one digit lower than brequinar. Theoretical design, modelling, synthesis, SAR, X-ray crystallographic data, biological assays, drug-like proprieties and in vivo toxicity are here presented and discussed.