title: Developing potent human uric acid transporter 1 (hURAT1) inhibitors.
abstract: 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 (14)C-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.
authors: School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States. Michael.Wempe@ucdenver.edu
authors: Michael F
authors: MF
authors: Wempe
authors: Promsuk
authors: P
authors: Jutabha
authors: Bettina
authors: B
authors: Quade
authors: Timothy J
authors: TJ
authors: Iwen
authors: Morin M
authors: MM
authors: Frick
authors: Ian R
authors: IR
authors: Ross
authors: Peter J
authors: PJ
authors: Rice
authors: Naohiko
authors: N
authors: Anzai
authors: Hitoshi
authors: H
authors: Endou
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D014981:Xenopus
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human