3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3.

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Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA

3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: highly potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase AKR1C3.

J Med Chem. 2012 Sep 13;55(17):7746-58. doi: 10.1021/jm3007867. Epub 2012 Aug 21.

PubMed ID
22877157 [ View in PubMed
]
Abstract

A high-throughput screen identified 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acid as a novel, highly potent (low nM), and isoform-selective (1500-fold) inhibitor of aldo-keto reductase AKR1C3: a target of interest in both breast and prostate cancer. Crystal structure studies showed that the carboxylate group occupies the oxyanion hole in the enzyme, while the sulfonamide provides the correct twist to allow the dihydroisoquinoline to bind in an adjacent hydrophobic pocket. SAR studies around this lead showed that the positioning of the carboxylate was critical, although it could be substituted by acid isosteres and amides. Small substituents on the dihydroisoquinoline gave improvements in potency. A set of "reverse sulfonamides" showed a 12-fold preference for the R stereoisomer. The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Flufenamic acidAldo-keto reductase family 1 member C3IC 50 (nM)410N/AN/ADetails
IndomethacinAldo-keto reductase family 1 member C3IC 50 (nM)2300N/AN/ADetails
IndomethacinAldo-keto reductase family 1 member C3IC 50 (nM)730N/AN/ADetails