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Updated: Sep 11, 2026

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions
Published on: July 28, 2022
Rational Design of Azaindole Derivatives via a Nitrogen-Walk Strategy from β-Carboline: Discovery of Highly
Yuxin Jiang1, Xiaoyu Shi1, Zhenkun Wu2
1Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Shandong Basic Science Special Academic Zone (Pharmacy), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong250012, P. R. China.
Abstract:
Hyperuricemia-induced gout is largely driven by impaired renal urate excretion, while current URAT1 inhibitors suffer from OAT1-mediated off-target toxicity. Our lead compound E1 potently inhibited URAT1 (IC50 = 3.02 μM) and reduced serum uric acid but exhibited OAT1 inhibition (IC50 = 4.78 μM) and HK-2 cytotoxicity (CC50 = 46.22 μM). To improve selectivity while retaining the core pharmacophore, a nitrogen-walk strategy was applied to design 48 azaindole derivatives. Pyrrolo[3,2-d]pyrimidine-based compound 17 was identified as the optimized candidate, exhibiting URAT1 inhibition (IC50 = 5.32 μM) with reduced OAT1 inhibition (IC50 = 30.11 μM), achieving a 6.7-fold selectivity improvement over E1. Compound 17 reduced serum uric acid by 77.7% at 2 mg/kg in an acute hyperuricemia mouse model and alleviated hepatic and renal injury in a chronic hyperuricemia model. It exhibited favorable druggability, including 87.9% oral bioavailability, a minimum effective dose below 0.5 mg/kg, and no observable toxicity up to 1000 mg/kg.
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