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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Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
Flufenamic acidAldo-keto reductase family 1 member C3IC 50 (nM)50N/AN/ADetails
Flufenamic acidProstaglandin G/H synthase 2IC 50 (nM)16N/AN/ADetails
ZopolrestatAldo-keto reductase family 1 member B10IC 50 (nM)2360N/AN/ADetails
ZopolrestatAldose reductaseIC 50 (nM)27N/AN/ADetails