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

Article


Flanagan, Jack U., Atwell, Graham J., Heinrich, Daniel M., Brooke, Darby G., Silva, Shevan, Rigoreau, Laurent J.M., Trivier, Elisabeth, Turnbull, Andrew P., Raynham, T., Jamieson, Stephen M.F. and Denny, William A. 2014. Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3). Bioorganic & Medicinal Chemistry. 22 (3), pp. 967-977.
AuthorsFlanagan, Jack U., Atwell, Graham J., Heinrich, Daniel M., Brooke, Darby G., Silva, Shevan, Rigoreau, Laurent J.M., Trivier, Elisabeth, Turnbull, Andrew P., Raynham, T., Jamieson, Stephen M.F. and Denny, William A.
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 ∼ 100 nM) 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.

JournalBioorganic & Medicinal Chemistry
Journal citation22 (3), pp. 967-977
ISSN09680896
Year2014
PublisherElsevier
Digital Object Identifier (DOI)doi:10.1016/j.bmc.2013.12.050
Web address (URL)https://doi.org/10.1016/j.bmc.2013.12.050
Publication dates
Print02 Jan 2014
Publication process dates
Deposited09 Aug 2017
Accepted21 Dec 2013
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