3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-尾-Hydroxysteroid Dehydrogenase AKR1C3

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• 作者：Stephen M. F. Jamieson ; Darby G. Brooke ; Daniel Heinrich ; Graham J. Atwell ; Shevan Silva ; Emma J. Hamilton ; Andrew P. Turnbull ; Laurent J. M. Rigoreau ; Elisabeth Trivier ; Christelle Soudy ; Sharon S. Samlal ; Paul J. Owen ; Ewald Schroeder ; Tony Raynham ; Jack U. Flanagan ; William A. Denny
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7746-7758
• 全文大小：613K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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 鈥渞everse sulfonamides鈥?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.