New structural scaffold discovery via fragment-based drug design: Hydroxymethyl indazole derivatives as XOR/URAT1 dual inhibitors

Otani N, Ouchi M, Mizuta E, Morita A, Fujita T, Anzai N, et al. Dysuricemia-a new concept encompassing hyperuricemia and hypouricemia. Biomedicines. 2023;11:1255.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021;397:1843–55.

Article  CAS  PubMed  Google Scholar 

Sun L, Zhang M, Zhao JX, Chen W, Wang G, The human gut microbiota and uric acid metabolism: genes, metabolites, and diet. Crit Rev Food Sci Nutr. 2025: 1-21.

Song D, Zhao X, Wang F, Wang G. A brief review of urate transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia and gout: current therapeutic options and potential applications. Eur J Pharm. 2021;907:174291.

Article  CAS  Google Scholar 

Sun ZQ, Zhang XW, Zhao ZA, Li X, Pang J, Chen J. Recent progress and future perspectives on anti-hyperuricemic agents. J Med Chem. 2024;67:19966–87.

Article  CAS  PubMed  Google Scholar 

Du L, Zong Y, Li HR, Wang Q, Xie L, Yang B, et al. Hyperuricemia and its related diseases: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9:212.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Perez-Ruiz F, Dalbeth N. Combination urate-lowering therapy in the treatment of gout: What is the evidence?. Semin Arthritis Rheum. 2019;48:658–68.

Article  CAS  PubMed  Google Scholar 

Shi XY, Zhao T, da Silva-Júnior EF, Zhang J, Xu S, Gao S, et al. Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2020-present). Expert Opin Ther Pat. 2022;32:1175–84.

Article  CAS  PubMed  Google Scholar 

Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017;69:1903–13.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Presa M, Pérez-Ruiz F, Oyagüez I. Second-line treatment with lesinurad and allopurinol versus febuxostat for management of hyperuricemia: a cost-effectiveness analysis for Spanish patients. Clin Rheumatol. 2019;38:3521–8.

Article  PubMed  Google Scholar 

Xue X, Sun M, Yan F, Dalbeth N, He Y, Li X, et al. Superiority of low-dose benzbromarone add-on to low-dose febuxostat compared with febuxostat monotherapy in gout with combined-type hyperuricemia. Arthritis Care Res(Hoboken). 2024;76:703–11.

Article  CAS  PubMed  Google Scholar 

Terkeltaub R, Lee J, Min J, Shin S, Saag KG. Serum urate-lowering efficacy and safety of tigulixostat in gout patients with hyperuricemia: a randomized, double-blind, placebo-controlled, dose-finding trial. Arthritis Rheumatol. 2023;75:1275–84.

Article  CAS  PubMed  Google Scholar 

Otani N, Ouchi M, Kudo H, Tsuruoka S, Hisatome I, Anzai N. Recent approaches to gout drug discovery: an update. Expert Opin Drug Discov. 2020;15:943–54.

Article  CAS  PubMed  Google Scholar 

Warrell RP, Klukovits A, Barnes K, Satyanarayana C, Cheeseman C, Piwinski P, et al. Profound hypouricemia induced in human subjects by novel bifunctional inhibitors of xanthine oxidase and URAT1. Arthritis Rheum. 2014;66:S366–S366.

Google Scholar 

Tonghua Dongbao Pharmaceuticals Completion of Phase IIa Clinical Trial Summary Report for Gout Dual-Target Inhibitor (THDBH151 Tablets) [Online]. Changchun, China: Tonghua Dongbao Pharmaceuticals; 2024. http://www.thdb.com/companynews-show-505.html (accessed July 1, 2024).

Zhu XY, Yang C, Zhang L, Jing L. Identification of novel dual inhibitors targeting XOR and URAT1 via multiple virtual screening methods. J Mol Struct. 2022;1256:132567.

Article  CAS  Google Scholar 

Zhu XY, Chen HM, Zhang L, Qin YX, Li J. Design, synthesis, and evaluation of the in vitro activity of novel dual inhibitors of XOR and URAT1 containing a benzoic acid group. Chem Biol Drug Des. 2023;102:1553–67.

Article  CAS  PubMed  Google Scholar 

Jhoti H, Williams G, Rees DC, Murray CW. The ‘rule of three’ for fragment-based drug discovery: where are we now?. Nat Rev Drug Discov. 2013;12:644–5.

Article  CAS  PubMed  Google Scholar 

Storer RI, Owen RM, Pike A, Benn CL, Armstrong E, Blakemore DC, et al. The discovery and evaluation of diaryl ether heterocyclic sulfonamides as URAT1 inhibitors for the treatment of gout. Medchemcomm. 2016;7:1587–95.

Article  CAS  Google Scholar 

Cai WQ, Wu JW, Liu W, Xie Y, Liu Y, Zhang S, et al. Systematic Structure-Activity Relationship (SAR) exploration of diarylmethane backbone and discovery of a highly potent novel Uric Acid Transporter 1 (URAT1) inhibitor. Molecules. 2018;23:252.

Article  PubMed  PubMed Central  Google Scholar 

Tian H, Liu W, Zhou Z, Shang Q, Liu Y, Xie Y, et al. Discovery of a flexible triazolylbutanoic acid as a highly potent Uric Acid Transporter 1 (URAT1) inhibitor. Molecules. 2016;21:1543.

Article  PubMed  PubMed Central  Google Scholar 

Yang XT, Pang XH, Fan L, Li X, Chen Y. Synthesis and evaluation of sulfonamide derivatives as potent Human Uric Acid Transporter 1 (hURAT1) inhibitors. Bioorg Med Chem Lett. 2017;27:1919–22.

Article  CAS  PubMed  Google Scholar 

Wu JW, Yin L, Liu YQ, Zhang H, Xie YF, Wang RL, et al. Synthesis, biological evaluation and 3D-QSAR studies of 1,2,4-triazole-5-substituted carboxylic acid bioisosteres as uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia associated with gout. Bioorg Med Chem Lett. 2019;29:383–8.

Article  CAS  PubMed  Google Scholar 

Peng JB, Hu QY, Gu CY, Liu B, Jin F, Yuan J, et al. Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model. Bioorg Med Chem Lett. 2016;26:277–82.

Article  CAS  PubMed  Google Scholar 

Li J, Wu FP, Liu XG, Zou Y, Chen H, Li Z. Synthesis and bioevaluation of 1-phenyl-pyrazole-4-carboxylic acid derivatives as potent xanthine oxidoreductase inhibitors. Eur J Med Chem. 2017;10:20–30.

Article  Google Scholar 

Zhou HY, Zhong GR, Bai J, Li X, Peng W, Zhang L, et al. Development of a fluorescence-based assay for screening of urate transporter 1 inhibitors using 6-carboxyfluorescein. Anal Biochem. 2021;626:114246.

Article  CAS  PubMed  Google Scholar 

Comments (0)

No login
gif