Discovery and Optimization of 6‑Azaindole URAT1 Inhibitors to Address Kidney and Liver Related Toxicities

Gout is a metabolic disorder characterized by excessive uric acid accumulation, often managed by uric acid transporter 1 (URAT1) inhibitors. However, existing URAT1 inhibitors such as lesinurad and benzbromarone present significant kidney and liver toxicity risks, respectively. To address these limitations, we designed and optimized a novel series of 6-azaindole URAT1 inhibitors, culminating in the lead candidate 22k. 22k demonstrated a favorable pharmacokinetic (PK) profile with a lower peak-to-trough ratio compared to lesinurad, suggesting slower renal clearance and a reduced risk of uric acid microcrystallization in the kidneys. Additionally, 22k exhibited no glutathione (GSH) trapping, unlike benzbromarone, indicating reduced risk of reactive metabolites formation and a lower potential for idiosyncratic liver toxicity. These findings highlight 22k as a promising next-generation URAT1 inhibitor with improved safety profile, warranting further investigations.