Background/Purpose: Hyperuricemia, abnormally elevated level of serum uric acid, is associated with gout as well as other diseases including metabolic syndrome, hypertension, diabetic kidney disease. In particular, hyperuricemia has causative link with gout, a metabolic disease characterized by deposition of sodium urate crystals in the joints and recurrent attacks of painful inflammatory arthritis. The therapeutic options for hyperuricemia/gout include xanthine oxidase inhibitors and uricosurics. Benzbromarone, probenecid and lesinurad are clinically available uricosurics, which increase the renal urate excretion by inhibiting URAT1, the transporter responsible for urate reabsorption. However, they are not widely used due to safety concern. In this study, we describe a novel URAT1 inhibitor, TEI-A, with a potent and highly selective properties.

Methods: Human URAT10overexpressing cells were treated with TEI-A, benzbromarone or lesinurad, and the uptake amounts of the specific substrates were measured to determine the inhibitory activities against the transporters. To determine the selectivity of TEI-A to URAT1, OAT1, OAT3 or OAT4-overexpressing cells, or ABCG2-overexpressing vesicles were treated with TEI-A, and the uptake amounts of the specific substrates were measured. Male tufted capuchin monkeys were administrated once orally with TEI-A (0.1-10 mg/kg), benzbromarone (3-30 mg/kg) and lesinurad (30 and 100 mg/kg). The fractional excretion of uric acid and serum uric acid level up to 24 hours after dosing were measured to determine uricosuric effects.

Results: In in vitro assays, TEI-A showed concentration-dependent inhibition of human URAT1-specific uptake of uric acid with IC₅₀ value of 14.3 ± 0.5 nmol/L. Inhibitory activity of TEI-A against URAT1 was 18-fold and 1600-fold stronger than those of benzbromarone and lesinurad, respectively. In addition, TEI-A showed highly selective to URAT1 over OAT1, 3, 4 and ABCG2. In tufted capuchin monkeys, TEI-A dose-dependently increased fractional excretion of uric acid up to 24 hours after dosing. Uricosuric effects of TEI-A were significantly stronger than those of benzbromarone and lesinurad. TEI-A also lowered serum uric acid level in tufted capuchin monkeys.

Conclusion: TEI-A is a potent and highly selective URAT1 inhibitor, and has greater uricosuric effects than benzbromarone and lesinurad in monkeys. TEI-A is a promising candidate for the treatment of patients with hyperuricemia and gout.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-selective-urat1-inhibitor-tei-a-with-potent-uricosuric-property/