Targeting Myeloid Differentiation Using Potent 2‑Hydroxypyrazolo[1,5‑<i>a</i>]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

Human dihydroorotate dehydrogenase (<i>h</i>DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. <i>h</i>DHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of <i>h</i>DHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo­[1,5-<i>a</i>]­pyridine, that has been designed starting from brequinar, one of the most potent <i>h</i>DHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound <b>4</b>, which shows brequinar-like <i>h</i>DHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound <b>4</b> also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of <i>h</i>DHODH inhibitors

Targeting Myeloid Differentiation Using Potent 2‑Hydroxypyrazolo[1,5‑<i>a</i>]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

Human dihydroorotate dehydrogenase (<i>h</i>DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. <i>h</i>DHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of <i>h</i>DHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo­[1,5-<i>a</i>]­pyridine, that has been designed starting from brequinar, one of the most potent <i>h</i>DHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound <b>4</b>, which shows brequinar-like <i>h</i>DHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound <b>4</b> also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of <i>h</i>DHODH inhibitors