Desing di nuovi inibitori della diidroorotato deidrogenasi umana: analoghi di MEDS433.

Human dihydroorotate dehydrogenase (hDHODH) is the fourth and rate-limiting enzyme in the de novo biosynthesis of pyrimidines1 and it is a validated target for the treatment of autoimmune disease, solid tumour, acute myeloid leukaemia (AML), and recently viral infectious diseases. In recent years, our research group discovered a new class of hDHODH inhibitors based on the hydroxypyrazolo[1,5-a]pyridine scaffold and MEDS433 is the most representative compound of the family.2 Despite its potency activity in vitro on isolated enzyme (IC₅₀ = 1.2 nM), comparable to that of Brequinar (IC₅₀ = 1.8 nM) and its highly selective on-target activity, this emergent compound has been found to have a low solubility that could be improved. Starting from MEDS433 was developed a new series, among them MEDS613 (IC₅₀ = 4.1 nM) was characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 μM). However, for MEDS613 a fast metabolism was observed, and after 30 min the parent compound was no longer present. Starting from these previous results, the purpose of this Master Thesis project was to investigate two different strategies. The first one was to enhance the metabolic stability of MEDS613 by blocking the β-hydroxylation of the propoxy chain, replacing the β-position with a carbonyl group or with two fluorine atoms. The second strategy of this work was to improve the solubility of MEDS433, in this case, we investigated the roles of the amide and hydroxyl groups replaced with a reverse amide and methyl sulfonyl group respectively.