Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17beta-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships.
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Adeniji AO, Twenter BM, Byrns MC, Jin Y, Chen M, Winkler JD, Penning TM
Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17beta-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships.
J Med Chem. 2012 Mar 8;55(5):2311-23. doi: 10.1021/jm201547v. Epub 2012 Feb 15.
- PubMed ID
- 22263837 [ View in PubMed]
- Abstract
Aldo-keto reductase 1C3 (AKR1C3; type 5 17beta-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5alpha-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5alpha-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.
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) 50 N/A N/A Details Flufenamic acid Prostaglandin G/H synthase 2 IC 50 (nM) 16 N/A N/A Details Zopolrestat Aldo-keto reductase family 1 member B10 IC 50 (nM) 2360 N/A N/A Details Zopolrestat Aldose reductase IC 50 (nM) 27 N/A N/A Details