Novel Steroid Inhibitors of Glucose 6-Phosphate Dehydrogenase

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• 作者：Niall M. Hamilton ; Martin Dawson ; Emma E. Fairweather ; Nicola S. Hamilton ; James R. Hitchin ; Dominic I. James ; Stuart D. Jones ; Allan M. Jordan ; Amanda J. Lyons ; Helen F. Small ; Graeme J. Thomson ; Ian D. Waddell ; Donald J. Ogilvie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4431-4445
• 全文大小：510K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3尾-alcohol can be replaced with 3尾-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.