Identification of a novel xanthine oxidoreductase inhibitor for hyperuricemia treatment with high efficacy and safety profile.

Autor: Li X; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Chen D; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Qi C; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Yang Y; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Guo K; Department of Pharmaceutical Analysis, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Ma C; Department of Pharmaceutical Analysis, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Tian J; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Li J; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Zhang L; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China., Wang B; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: wangbaolian@imm.ac.cn., Xiao Z; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: xiaoz@imm.ac.cn., Ye F; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: yefei@imm.ac.cn.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Sep; Vol. 178, pp. 117223. Date of Electronic Publication: 2024 Aug 01.
DOI: 10.1016/j.biopha.2024.117223
Abstrakt: Hyperuricemia is with growing incidence and of high risk to develop into gout and other metabolic diseases. The key enzyme catalyzing uric acid synthesis, xanthine oxidoreductase (XOR) is a vital target for anti-hyperuricemic drugs, while XOR inhibitors characterized as both potent and safe are currently in urgent need. In this study, a novel small molecule compound, CC15009, was identified as a specific XOR inhibitor. CC15009 exerted strongest in vitro XOR inhibitory activity among current XOR inhibitors. It also showed favorable dose-dependent uric acid-lowering effects in two different XOR substrate-induced hyperuricemic mouse models, which was significantly superior than the current first-line drug, allopurinol. Mechanically, the direct binding of CC15009 against XOR was confirmed by molecular docking and SPR analysis. The inhibition mode was competitive and reversible. Besides, the potential antioxidant activity of CC15009 was indicated by its strong inhibitory activity against the oxidized isoform of XOR, which reduced ROS generation as the byproduct. Regarding the safety concerns of current XOR inhibitors, especially in cardiovascular risks, the safety of CC15009 was comprehensively evaluated. No significant abnormality was observed in the acute, subacute toxicity tests and mini-AMES test. Notably, there was no obvious inhibition of CC15009 against cardiac ion channels, including hERG, Na v 1.5, Ca v 1.2 at the concentration of 30 μM, indicating its lower cardiovascular risk. Taken together, our results supported CC15009 as a candidate of high efficacy and safety profile to treat hyperuricemia through direct XOR inhibition.
Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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