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.

中文翻译：

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3-（3,4-二氢异喹啉-2（1 H）-基磺酰基）苯甲酸：类型为517-β-羟基类固醇脱氢酶AKR1C3的高强度和选择性抑制剂

高通量筛选确定了3-（3,4-二氢异喹啉-2（1H）-基磺酰基）苯甲酸是一种新型，高效（低nM）和同工型选择性（1500倍）的醛酮还原酶抑制剂AKR1C3：乳腺癌和前列腺癌的关注靶标。晶体结构研究表明，羧酸盐基团占据了酶中的氧阴离子孔，而磺酰胺提供了正确的捻度，以允许二氢异喹啉在相邻的疏水口袋中结合。围绕该铅的SAR研究表明，羧酸盐的位置至关重要，尽管它可以被酸性等排物和酰胺取代。二氢异喹啉上的小取代基改善了效力。一组“逆磺酰胺”显示对R的偏好是其12倍立体异构体。通过抑制已知的二硝基苯甲酰胺底物的AKR1C3代谢来测量，该化合物显示出良好的细胞效能，在酶活性和细胞活性之间具有广泛的等级顺序，但是酰胺类似物比细胞测定所预测的更有效。