Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3)

Bioorg Med Chem. 2014 Feb 1;22(3):967-77. doi: 10.1016/j.bmc.2013.12.050. Epub 2014 Jan 2.


Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50∼100nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311.

Keywords: AKR; Aldo–keto reductase; COX; Computer aided drug design; Crystal structure; DCM; DIPEA; DMSO; Inhibitor; Morpholylureas; NADPH; NSAID; PBD; Protein Data Bank; TFA; aldo–keto reductase; cyclo-oxygenase; dichloromethane; diisopropylethylamine; dimethyl sulfoxide; nicotinamide adenine dinucleotide phosphate; non-steroidal anti-inflammatory drugs; trifluoroacetic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 3-Hydroxysteroid Dehydrogenases / chemistry
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • Aldo-Keto Reductase Family 1 Member C3
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hydrogen Bonding
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
  • Hydroxyprostaglandin Dehydrogenases / chemistry
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Morpholines / chemistry
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Morpholines
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3