A Novel Pyrrole Acylsulfonamide, Compound 42, as a Dual URAT1/GLUT9 Inhibitor: Potent Urate-Lowering Efficacy,
Zhenqian Wang1, Xiaoyu Shi1, Zitao Guo2
1Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P.R. China.
Abstract:
Hyperuricemia and gout remain challenging due to the limited efficacy and safety of current therapies. Herein, we report a novel pyrrole acylsulfonamide, compound 42, rationally designed via structural simplification of lead compounds E1 and ZS-24, targeting urate transporters. In acute hyperuricemia mice, compound 42 demonstrated potent urate-lowering efficacy with a decrease ratio of 88.76%, significantly superior to Lesinurad (39.02%). Mechanistically, it synergistically inhibited URAT1 (IC50 = 2.81 ± 0.40 μM) and GLUT9 (IC50 = 12.53 ± 1.33 μM), with reduced off-target activity on OAT1 (IC50 = 7.83 ± 0.70 μM vs ZS-24's 4.90 ± 0.99 μM) to mitigate potential toxicity. It displayed superior ligand efficiency (LE = 0.44 vs ZS-24's 0.41) and favorable pharmacokinetics (T1/2 = 5.55 h, F = 51.3%). In hyperuricemic nephropathy mice, compound 42 reduced serum uric acid and protected renal function without acute and subacute toxicity at high doses, supporting its promise as a candidate for hyperuricemia and gout.
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Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
