Important steps into drug development of MEDS433, a potent human dihydroorotate dehydrogenase inhibitor based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold

In 2018, using a bioisosteric approach supported by structure based techniques, we discovered MEDS433, based on the 2-hydroxypyrazolo[1,5-a]pyridine scaffold. This compound shown to be an inhibitor of the human Dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis (IC50 = 1.2 nM), potent, on isolated protein, like the reference compound Brequinar. Moreover in the late 2016 the connection between Acute Myelogenous Leukemia (AML) and hDHODH, has attracted significant interest from pharmaceutical companies who have recognized it as a new therapeutic target for AML. So we tested MEDS433 in AML cell lines (THP1 and U937) and it was able to induce myeloid differentiation in the low nM range (EC50 = 40 and 26 nM) and show better qualities than brequinar (EC50 = 249 nM on THP1 and 189 nM on U937). These incredible in vitro results encouraged us to start the process of Drug Development on MEDS433; we have measured ADME properties and started in vivo pharmacokinetics and toxicity studies on mice as well as efficacy tests in different leukemic xenograft mouse models. In this occasion the MEDS433 profile is presented. The strategy that allowed the discovery of MEDS700, a metabolically stable MEDS433 backup compound is also presented.