Developing Potent Human Uric Acid Transporter 1 (hURAT1) Inhibitors
Document Type
Article
Publication Date
4-28-2011
Description
The kidneys are a vital organ in the human body. They serve several purposes including homeostatic functions such as regulating extracellular fluid volume and maintaining acid-base and electrolyte balance and are essential regarding the excretion of metabolic waste. Furthermore, the kidneys play an important role in uric acid secretion/reabsorption. Abnormalities associated with kidney transporters have been associated with various diseases, such as gout. The current study utilized Xenopus oocytes expressing human uric acid transporter 1 (hURAT1; SLC22A12) as an in vitro method to investigate novel compounds and their ability to inhibit 14C-uric acid uptake via hURAT1. We have prepared and tested a series of 2-ethyl-benzofuran compounds and probed the hURAT1 in vitro inhibitor structure-activity relationship. As compared to dimethoxy analogues, monophenols formed on the C ring showed the best in vitro inhibitory potential. Compounds with submicromolar (i.e., IC 50 < 1000 nM) inhibitors were prepared by brominating the corresponding phenols to produce compounds with potent uricosuric activity.
Citation Information
Wempe, Michael F.; Jutabha, Promsuk; Quade, Bettina; Iwen, Timothy J.; Frick, Morin M.; Ross, Ian R.; Rice, Peter J.; Anzai, Naohiko; and Endou, Hitoshi. 2011. Developing Potent Human Uric Acid Transporter 1 (hURAT1) Inhibitors. Journal of Medicinal Chemistry. Vol.54(8). 2701-2713. https://doi.org/10.1021/jm1015022 PMID: 21449597 ISSN: 0022-2623