Novel steroid inhibitors of glucose 6-phosphate dehydrogenase.

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Hamilton NM, Dawson M, Fairweather EE, Hamilton NS, Hitchin JR, James DI, Jones SD, Jordan AM, Lyons AJ, Small HF, Thomson GJ, Waddell ID, Ogilvie DJ

Novel steroid inhibitors of glucose 6-phosphate dehydrogenase.

J Med Chem. 2012 May 10;55(9):4431-45. doi: 10.1021/jm300317k. Epub 2012 Apr 27.

PubMed ID

22506561 [ View in PubMed

]

Abstract

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 3beta-alcohol can be replaced with 3beta-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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
16-Bromoepiandrosterone	Glucose-6-phosphate 1-dehydrogenase	IC 50 (nM)	20800	N/A	N/A	Details