Scaling up synthesis and in vivo evaluation of MEDS433: a promising preclinical candidate targeting AML

Human Dihydroorotate Dehydrogenase (hDHODH) is a validate drug target associated with the metabolism of cancer cells. It is an important regulator of the de novo biosynthesis of pyrimidines and it has emerged as a new target able to induce cellular differentiation. In particular, extensive studies have shown that AML cells are very sensitive to the inhibition of this enzyme: the cells undergo to a condition of pyrimidine starvation that leads to the differentiation and then apoptosis of leukemic cells [1]. In recent years, the MedSynth Research group developed a novel class of hDHODH inhibitors based on hydroxypyrazolo[1,5-a]pyridine scaffold and MEDS433 is emerged as a potent pro-apoptotic agent in AML cells [2]. The MEDS433 high potency on isolated enzyme (IC50 hDHODH 1.2 nM) is translated into powerful effects at the cellular level. Considering the encouraging results obtained, MEDS433 stands out as the most favorable candidate for advancement into the preclinical development phase. Since integrate green chemistry principles in early drug development stages is crucial for maximizing benefits, the main objective of this work is to optimize the synthetic scheme prior to clinical trial authorization to prevent the need for future modifications and avoiding the necessity for GMP reassessment and additional clinical trials in an advanced phase. As a result, a more practical synthesis of MEDS433 in multi-gram quantities has been achieved and allowed the obtainment of promising in vivo efficacy, pharmacokinetic and toxicity data of the drug candidate.