Preliminary ADME/PK studies of new hDHODH inhibitors effective for treatment of acute myeloid leukaemia (AML)

The human Dihydroorotate Dehydrogenase (hDHODH) plays a pivotal role in de novo pyrimidine biosynthesis, controlling vital cellular functions and survival. Recently, hDHODH, a validated target for treatment of autoimmune diseases has related to acute myeloid leukaemia (AML), being hDHODH inhibitor able to restore the myeloid differentiation. We developed a new class of hDHODH inhibitors [1], being M433 (IC50 = 1.2 nM) the most interesting. In this occasion, we profiled these compounds for their physicochemical properties as drugs, i.e. lipophilicity, solubility, biological fluids stability, protein binding and in vitro metabolism. Compound M433 was also studied in vivo, in order to determinate its pharmacokinetic profile. We quantified plasma concentration of M433 by LC-MS/MS in MRM mode in female and male CD-1 mice, after a single intravenous dose (5 mg/Kg). Moreover, in vivo toxicity was evaluated in Balb mice, treated the animals for 35 days with two different doses of M433 (10 and 25 mg/Kg), all mice tissues were evaluated and compared to controls. Drug-like properties, pharmacokinetic and toxicity profile are presented and discussed. The data obtained will be useful for planning the design of the next generation of inhibitors, while future tests to determine the complete ADME-Tox profile.