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

Jack U Flanagan; Graham J Atwell; Daniel M Heinrich; Darby G Brooke; Shevan Silva; Laurent J M Rigoreau; Elisabeth Trivier; Andrew P Turnbull; Tony Raynham; Stephen M F Jamieson; William A Denny

doi:10.1016/j.bmc.2013.12.050

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.

Affiliations

¹ Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
² Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
³ Cancer Research Technology Ltd, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower St., London WC1E 6BT, UK.
⁴ Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.denny@auckland.ac.nz.

PMID: 24411201
DOI: 10.1016/j.bmc.2013.12.050

Abstract

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

Substances

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