Enhancement of the metabolic stability in 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based inhibitors of human dihydroorotate dehydrogenase (hDHODH)

Human dihydroorotate dehydrogenase (hDHODH), a pivotal enzyme in the de novo pyrimidine biosynthesis, stands as a validated target for the treatment of autoimmune diseases, solid tumors, and, more recently, acute myeloid leukemia (AML). By using a non-classic bioisosteric approach supported by structure-based drug design, we recently discovered MEDS613, a molecule 15-fold superior to brequinar, a known hDHODH inhibitor, in its cell-based in vitro potency. Unfortunately, MEDS613 suffered from poor in vitro metabolic stability, thus limiting further preclinical studies.[1] This work discloses the process of identification of MEDS613’s propoxy chain metabolic soft spot, which allowed the design of the new lead structure MEDS700, a metabolically stable candidate (whose hDHODH binding mode has been elucidated by x-ray crystallography) with comparable, or even better, performance than MEDS613 in terms of enzymatic inhibition, pro-apoptotic and pro-differentiating effects on AML cell lines (Figure 1). MEDS700 represents a promising candidate for further steps into the drug development process, thus, before future in vivo toxicity/efficacy studies, the pharmacokinetics profile has been also outlined and here fully discussed.