Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety

J Med Chem. 2022 Oct 13;65(19):12701-12724. doi: 10.1021/acs.jmedchem.2c00496. Epub 2022 Sep 26.


In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Dihydroorotate Dehydrogenase
  • Dipyridamole / therapeutic use
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Mice
  • Oxidoreductases Acting on CH-CH Group Donors*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Structure-Activity Relationship


  • Antiviral Agents
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • Pyridines
  • Dipyridamole
  • Oxidoreductases Acting on CH-CH Group Donors