Overcoming of metabolic issues in 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based inhibitors of human dihydroorotate dehydrogenase: the story of MEDS700

Human dihydroorotate dehydrogenase (hDHODH), a crucial enzyme in the de novo pyrimidine biosynthesis, is a validated target for treating autoimmune diseases, solid tumors, and, more recently, acute myieloid leukemia (AML).[1] Through a non-classical bioisosteric approach supported by structure-based drug design, our research group recently discovered MEDS613, a molecule exhibiting 15-fold greater potency in cell-based assays compared to brequinar, a known hDHODH inhibitor. Unfortunately, MEDS613 suffered from poor in vitro metabolic stability, thus limiting further preclinical studies.[2] This work unveils the identification process of MEDS613's alkoxy chain metabolic soft spot, which finally led to the design of MEDS700, a metabolically stable analogue. MEDS700, whose hDHODH binding mode has been elucidated through x-ray crystallography, demonstrates comparable or even improved performance to MEDS613, in terms of enzymatic inhibition and pro-apoptotic and pro-differentiating induction on AML cell lines. MEDS700 represents a promising candidate for further steps in the drug development process, thus, prior to future in vivo toxicity/efficacy studies, the pharmacokinetic profile of the new lead compound has been outlined and here fully discussed.