化学
立体化学
苯甲酸
酰胺
羧酸盐
酶
羟类固醇脱氢酶
基质(水族馆)
磺胺
IC50型
取代基
还原酶
CYP3A4型
脱氢酶
生物化学
体外
细胞色素P450
地质学
海洋学
作者
Stephen M.F. Jamieson,Darby G. Brooke,Daniel Heinrich,Graham J. Atwell,Shevan Silva,Emma Hamilton,A.P. Turnbull,Laurent Rigoreau,Elisabeth Trivier,Christelle Soudy,S.S. Samlal,Paul Owen,Ewald Schroeder,Tony Raynham,Jack U. Flanagan,William A. Denny
摘要
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.
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