An evaluation method for uric acid uptake inhibition using primary human proximal tubule epithelial cells treated with insulin.

The effects of uricosuric agents have been evaluated with indices of uric acid uptake into human urate transporter 1 (URAT1)-overexpressed oocytes or cells. In the present study, we evaluated a method using primary human renal proximal tubule epithelial cells (RPTECs). Pretreatment of RPTECs with insulin significantly increased the uptake of uric acid into these cells.

Novel monocyclic amide-linked phenol derivatives without mitochondrial toxicity have potent uric acid-lowering activity.

Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal tubule epithelial cells.

Discovery of Dotinurad (FYU-981), a New Phenol Derivative with Highly Potent Uric Acid Lowering Activity.

To derive new uricosuric agents, novel phenol derivatives were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivatives with a 1,1-dioxo-1,2-dihydro-3-1,3-benzothiazole scaffold. The selected compound (dotinurad, FYU-981) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration.

Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor.

Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0.