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.
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Heinrich DM, Flanagan JU, Jamieson SM, Silva S, Rigoreau LJ, Trivier E, Raynham T, Turnbull AP, Denny WA
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.
Eur J Med Chem. 2013 Apr;62:738-44. doi: 10.1016/j.ejmech.2013.01.047. Epub 2013 Feb 9.
- PubMed ID
- 23454516 [ View in PubMed]
- Abstract
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 (<100 nM) and isoform-selective non-carboxylate inhibitors of AKR1C3. Structure-activity relationships identified the sulfonamide was critical, and a crystal structure showed the 2-pyrrolidinone does not interact directly with residues in the oxyanion hole. Variations in the position, co-planarity or electronic nature of the pyrrolidinone ring severely diminished activity, as did altering the size or polarity of the piperidino ring. There was a broad correlation between the enzyme potencies of the compounds and their effectiveness at inhibiting AKR1C3 activity in cells.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Flufenamic acid Aldo-keto reductase family 1 member C3 IC 50 (nM) 410 N/A N/A Details Flufenamic acid Prostaglandin G/H synthase 1 IC 50 (nM) 3000 N/A N/A Details Flufenamic acid Prostaglandin G/H synthase 2 IC 50 (nM) 9300 N/A N/A Details Meclofenamic acid Prostaglandin G/H synthase 1 IC 50 (nM) 220 N/A N/A Details Meclofenamic acid Prostaglandin G/H synthase 2 IC 50 (nM) 700 N/A N/A Details Mefenamic acid Prostaglandin G/H synthase 1 IC 50 (nM) 25000 N/A N/A Details Mefenamic acid Prostaglandin G/H synthase 2 IC 50 (nM) 2900 N/A N/A Details