Optimization of MEDS433 synthesis: scale-up for preclinical evaluation studies

MEDS433, it’s a novel preclinical candidate developed by the MEDSynth Research group, belongs to a novel class of hDHODH (human dihydroorotate dehydrogenase) inhibitors based on hydroxypyrazolo[1,5-a]pyridine scaffold. Extensive studies have shown its capability to induce myeloid differentiation and apoptosis in various AML (acute myeloid leukemia) cell lines, resulting in significant leukemic cell death [1]. Consequently, MEDS433 is emerging as an ideal candidate for further in vivo studies in AML models. In order to conduct a comprehensive biological evaluation of the drug candidate, it was necessary to obtain significant quantities of the compound for both in vitro and in vivo efficacy, pharmacokinetic and toxicity studies. Concurrently, implementing eco-sustainable approaches in the early stages of drug development is crucial [2]. This step is necessary prior to submitting the clinical trial authorization request to regulatory agencies to prevent the need for repeating GMP evaluation and clinical trials. This work highlights the resolution of critical issues associated with the synthesis of the drug candidate adopting greener approaches that permitted the elimination of chromatography purifications and the reduction in process waste containing by-products. Through process improvements and optimization of various steps in the synthetic scheme, a more practical and cost-effective synthesis of MEDS433 in multi-gram quantities has been achieved.