title: Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3).
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.
authors.affiliation: 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.
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Atwell
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Heinrich
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Darby G
authors.initials: DG
authors.lastname: Brooke
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Shevan
authors.initials: S
authors.lastname: Silva
authors.affiliation: Cancer Research Technology Ltd, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower St., London WC1E 6BT, UK.
authors.forename: Laurent J M
authors.initials: LJ
authors.lastname: Rigoreau
authors.affiliation: Cancer Research Technology Ltd, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower St., London WC1E 6BT, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Trivier
authors.affiliation: Cancer Research Technology Ltd, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower St., London WC1E 6BT, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Turnbull
authors.affiliation: Cancer Research Technology Ltd, Wolfson Institute for Biomedical Research, The Cruciform Building, Gower St., London WC1E 6BT, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Raynham
authors.affiliation: 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.
authors.forename: Stephen M F
authors.initials: SM
authors.lastname: Jamieson
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009025:Morpholines; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3
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