Background/Purpose: AR882 is a potent and selective inhibitor of uric acid transporter 1 (URAT1), which is responsible for a majority of reabsorption of filtered uric acid from the renal tubular lumen. By inhibiting URAT1, AR882 increases uric acid urinary excretion and thereby lowers serum uric acid (sUA). Preclinically, AR882 has demonstrated inhibitory effect on uric acid uptake and good tolerability in pharmacology, pharmacokinetic and toxicology studies.

Methods: The inhibition of AR882 on human URAT1-mediated uptake of [¹⁴C]uric acid was studied in Madin-Darby Canine Kidney (MDCKII) cells expressing human URAT1. Inhibitory potential to human organic anion transporter (OAT) 4, a transporter reported involving uric acid uptake, was also tested in human embryonic kidney (HEK) 293 cells expressing human OAT4. Absorption, distribution, excretion of AR882 were evaluated following single oral or intravenous administration in multiple species. Metabolic stability of AR882 was evaluated in microsomes and hepatocytes in vitro across species including human and in vivo in rats, dogs and monkeys.  Drug-drug interaction (DDI) evaluations with major renal transporters were conducted in HEK293 cells expressing P-glycoprotein, OAT1, OAT3, OAT4, and organic cation transporter 2 (OCT2) transporters. Toxicity and toxicokinetics of AR882 were assessed following oral repeat-dose administration to Sprague-Dawley rats and cynomolgus monkeys for durations up to 4 weeks.

Results: AR882 exhibited high potency against URAT1 with an IC₅₀ of 67 nM, compared to lesinurad (IC₅₀ = 7.3 µM, Zurampic® Package Insert) or benzbromarone (IC₅₀ = 196 nM). An IC₅₀ of 2.89 µM against OAT4 indicated that AR882 is highly selective for URAT1. AR882 was well absorbed in rats, dogs, and monkeys, with a mean T_max of 1‑2 hours. Bioavailability ranged between 76% and 88% across the tested species. In vitro metabolic profiling and in vivo clearance suggesting AR882 is extremely stable. In animals, unchanged parent compound was recovered in the urine at concentrations sufficient for complete inhibition of URAT1.   Transporter evaluations with major efflux and uptake transporter in kidney revealed no DDI potential and no active-transportation involvement.  Using allometric scaling, a low therapeutic dose of AR882 is anticipated in human.  Rats and monkeys were selected as the species for toxicology evaluation based on metabolic profiling. In 4-week oral repeat-dose toxicology and toxicokinetic studies, AR882 was well tolerated at doses up to 50 mg/kg/day and 150 mg/kg/day in rats and monkeys, respectively. The exposures achieved in animals were substantially higher than the observed human exposure at the anticipated therapeutic doses of 25 mg – 100 mg in clinical study

Conclusion: AR882, a selective URAT1 inhibitor with superb potency for URAT1-mediated uric acid reabsorption has been discovered and developed for the treatment of gout at a low anticipated daily dose. AR882 exhibited favorable pharmacokinetic and DDI properties, as well as an excellent safety profile in preclinical studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ar882-a-potent-and-selective-urat1-inhibitor-with-a-favorable-pharmacological-pharmacokinetic-and-toxicity-profile/