Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3

High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose tr...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2013-04, Vol.62, p.738-744
Main Authors: Heinrich, Daniel M, Flanagan, Jack U, Jamieson, Stephen M F, Silva, Shevan, Rigoreau, Laurent J M, Trivier, Elisabeth, Raynham, Tony, Turnbull, Andrew P, Denny, William A
Format: Article
Language:English
Subjects:
3-Hydroxysteroid Dehydrogenases - antagonists & inhibitors
3-Hydroxysteroid Dehydrogenases - metabolism
Aldo-Keto Reductase Family 1 Member C3
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
HCT116 Cells
Humans
Hydroxyprostaglandin Dehydrogenases - antagonists & inhibitors
Hydroxyprostaglandin Dehydrogenases - metabolism
Models, Molecular
Molecular Structure
Pyrrolidinones - chemical synthesis
Pyrrolidinones - chemistry
Pyrrolidinones - pharmacology
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary:High expression of the aldo-keto reductase enzyme AKR1C3 in the human prostate and breast has implicated it in the development and progression of leukemias and of prostate and breast cancers. Inhibitors are thus of interest as potential drugs. Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes. We describe here a series of (piperidinosulfonamidophenyl)pyrrolidin-2-ones as potent (
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.01.047