Rational Design of Azaindole Derivatives via a Nitrogen-Walk Strategy from β-Carboline: Discovery of Highly Selective, Low-Toxicity URAT1 Inhibitors as Potent Urate-Lowering Agents
Yuxin Jiang, Xiaoyu Shi, Zhenkun Wu, Qian Yang, Shujing Xu, Zeqi Yu, Mingyu Yang, Mei Wang, Zhiyong Liu, Weiting Meng, Ting Wu, Xinyong Liu, Jianxin Pang, Fan Yi, Peng ZhanAbstract
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.