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, 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/re-absorption. 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 (SAR). Compared to di-methoxy analogs, mono-phenols formed on the C-Ring showed the best in vitro inhibitory potential. Compounds with sub-micromolar (i.e. IC50 < 1000 nM) inhibitors were prepared by brominating the corresponding phenols to produce compounds with potent uricosuric activity.

Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies

“…As illustrated in Figure 1, we probed three different benzofuran templates (I, II, and III) and their ability to inhibit 14 C-urate uptake in oocytes expressing hURAT1. Our previous work provided important insights regarding required chemical features; in summary, the data supported the notion that an anion (preferably on the C-ring; Figure 1) is required in order to interact with a positively charged hURAT1 binding pocket 10,11. The previous studies also demonstrated how electronic donating and/or withdrawing groups attached to the B-ring influence inhibitory potency.…”

“…We also prepared butyl analogs (17) and (18). Nonhalogenated butyl analog (17) was a much weaker inhibitor than the corresponding ethyl analog 10. Compound (18) (1932 nM) compared with (1) (26 nM) also clearly demonstrates the alkyl chain modification effect.…”

“…We believe that designing potent uric acid transporter inhibitors may lead to novel therapeutic agents. Our previous works have described chemical synthesis and in vitro testing that produced important hURAT1 structure–activity relationship (SAR) data 10,11. As illustrated in Figure 1, we probed three different benzofuran templates (I, II, and III) and their ability to inhibit 14 C-urate uptake in oocytes expressing hURAT1.…”

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

“…1) that acts as a uricosuric agent by inhibiting urate reabsorption (Shin et al, 2011). Both BBR and 6-hydroxy BBR (a metabolite of BBR) have been reported to show potent human uric acid transporter 1 inhibition property (Wempe et al, 2011), which has made BBR a quite useful antigout agent for approximately 30 years in many countries. More recently, however, clinical cases of acute liver damage, including some fatalities related to BBR (Wagayama et al, 2000;Arai et al, 2002;Reinders et al, 2007), have drawn our attention to the metabolism profiles of BBR.…”

Application of anin vitroOAT assay in drug design and optimization of renal clearance

“…OAT4 (in the apical membrane of human proximal tubule cells) contributes to drug exit into the lumen and to uptake of estrone sulfate and urate from the lumen into the cell. URAT1 is the major urate-absorbing transporter in the apical membrane and is of interest as a drug target for gout (Wempe et al, 2011), while other family members may be of future interest as drug targets for chronic kidney disease, given the recognition of some nephrotoxins as substrates (Masereeuw & Russel, 2010). Understanding of the role of such transporters in drug disposition is key to the quantitative prediction of human clearance, particularly for acidic drugs, given their limited volume of distribution (often $0.2 l/kg) (McGinnity et al, 2007), and an assessment of inter-subject variability due to genetic and/or environmental factors, including drugdrug interactions.…”