Research progress in novel xanthine oxidase inhibitors and treatment of gout

doi:10.19803/j.1672-8629.20230584

Abstract

Abstract: Objective To summarize the recent progress in research on xanthine oxidase (XO) inhibitors. Methods Small molecule XO inhibitors were elaborated in terms of structural scaffold, molecular docking, activity and pharmacokinetics. Results Carboxylic acid and amide based XO inhibitors showed a favorable potential with activities comparable to those of topiroxostat, which could be a hotspot for future design of XO inhibitors. Conclusion It is expected that further structural optimization of carboxylic acids and amides will lead to the discovery of more effective XO inhibitors.

Key words: xanthine oxidase, inhibitors, gout, hyperuricemia, carboxylic acids, amides, purines, uric acid-lowering drugs

CLC Number:

R977

JIN Shengju, ZHOU Miao, ZHANG Jianing, GE Gonghui, ZHANG Tingjian, MENG Fanhao. Research progress in novel xanthine oxidase inhibitors and treatment of gout[J]. Chinese Journal of Pharmacovigilance, 2024, 21(2): 223-228.

Add to citation manager EndNote|Ris|BibTeX

URL: https://www.zgywjj.com/EN/10.19803/j.1672-8629.20230584

https://www.zgywjj.com/EN/Y2024/V21/I2/223

References

[1] LIN YX, HUANG YW, XIONG JH, et al.Research progress in drugs for treating gout[J]. Chinese Journal of Rural Medicine and Pharmacy(中国乡村医药), 2021, 28(24): 87-88.
[2] Chinese Medical Association Endocrinology Branch. Chinese guidelines for the diagnosis and treatment of hyperuricemia and gout (2019)[J]. Chinese Journal of Endocrinology and Metabolism(中华内分泌代谢杂志), 2020, 36(1): 1-13.
[3] NI Q.Guideline for diagnosis and treatment of hyperuricemia and gout (2021-01-20)[J]. World Chinese Medicine(世界中医药), 2021, 16(2): 183-189.
[4] FU HT, ZHANG M, CI XY, et al.Research progress of therapeutic agents for gout and hyperuricemia[J]. Drug Evaluation Research(药物评价研究), 2021, 44(8): 1811-1816.
[5] FANG NY, LYU LW, LYU XX, et al.China multi-disciplinary expert consensus on diagnosis and treatment of hyperuricemia and related diseases(2023 edition)[J]. Chinese Journal of Practical Internal Medicine(中国实用内科杂志), 2023, 43(6): 461-480.
[6] ZHANG XW.Several concerned issues in the treatment of gouty arthritis[J]. Journal of Peking University(Health Sciences)(北京大学学报医学版), 2021, 53(6): 1017-1019.
[7] CDR-ADR, NMPA. Febuxostat: updated advice for the treatment of patients with a history of major cardiovascular disease[EB/OL]. (2023-06-21)[2023-11-02]. https://www.cdr-adr.org.cn/drug_1/aqjs_1/drug_aqjs_jjkx/202306/t20230625_50246.html.
[8] CDR-ADR, NMPA. Adverse drug reaction information notification - alert to the risk of liver damage caused by benzbromarone[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2016, 13(1): 59-60.
[9] CICERO AFG, FOGACCI F, KUWABARA M, et al.Therapeutic strategies for the treatment of chronic hyperuricemia: an evidence-based update[J]. Medicina(Kaunas), 2021, 57(1): 58.
[10] FURUHASHI M.New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity[J]. Am J Physiol Endocrinol Metab, 2020, 319(5): E827-E834.
[11] LI WY, ZHAI N, JU XL, et al.Research progress of febuxostat derivatives as xanthine oxidase inhibitors[J]. Acta Pharmaceutica Sinica(药学学报), 2021, 56(12): 3401-3413.
[12] ZHAO Y, ZHANG QH, FENG MS, et al.Advances in the research of xanthine oxidase inhibitors for lowering urate[J]. Progress in Pharmaceutical Sciences(药学进展), 2009, 33(2): 55-61.
[13] KUMAR R, JOSHI G, KLER H, et al.Toward an understanding of structural insights of xanthine and aldehyde oxidases: an overview of their inhibitors and role in various diseases[J]. Med Res Rev, 2018, 38(4): 1073-1125.
[14] KIBRIZ İE, SAÇMACI M, YILDIRIM İ, et al. Xanthine oxidase inhibitory activity of new pyrrole carboxamide derivatives: in vitro and in silico studies[J]. Arch Pharm(Weinheim), 2018, 351(10): e1800165.
[15] ZHANG B, DAI X, BAO Z, et al.Targeting the subpocket in xanthine oxidase: design, synthesis, and biological evaluation of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives[J]. Eur J Med Chem, 2019, 181: 111559.
[16] YAGIZ G, NOMA SAA, ALTUNDAS A, et al.Synthesis, inhibition properties against xanthine oxidase and molecular docking studies of dimethyl N-benzyl-1H-1, 2, 3-triazole-4, 5-dicarboxylate and (N-benzyl-1H-1, 2, 3-triazole-4, 5-diyl) dimethanol derivatives[J]. Bioorganic Chemistry, 2021, 108: 104654.
[17] ZHOU H, LI X, LI Y, et al.Synthesis and bioevaluation of 1-phenylimidazole-4-carboxylic acid derivatives as novel xanthine oxidoreductase inhibitors[J]. European Journal of Medicinal Chemistry, 2020, 186: 111883.
[18] ZHANG T, TU S, ZHANG X, et al.Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: design, synthesis and structure-activity relationship investigation[J]. Bioorganic Chemistry, 2021, 117: 105417.
[19] TU S, ZHANG T J, ZHANG Y, et al.N-(3-cyano-1H-indol-5-yl) isonicotinamide and N-(3-cyano-1H-indol-5-yl)-1H-benzo [d] imidazole-5-carboxamide derivatives: Novel amide-based xanthine oxidase inhibitors[J]. Bioorganic Chemistry, 2021, 115: 105181.
[20] ZHANG TJ, ZHANG X, XU EY, et al.A possible covalent xanthine oxidase inhibitor TS10: inhibition mechanism, metabolites identification and PDPK assessment[J]. Bioorg Chem, 2022, 128: 106064.
[21] ZHANG T, ZHANG Z, ZHANG X, et al.Design, synthesis and biological evaluation of N-(4-alkoxy-3-(1H-tetrazol-1-yl) phenyl) heterocyclic aromatic amide derivatives as xanthine oxidase inhibitors[J]. Bioorganic Chemistry, 2022, 126: 105938.
[22] LI SY, ZHANG TJ, WU QX, et al.Synthesis and biological evaluation of 5-benzyl-3-pyridyl-1H-1,2,4-triazole derivatives as xanthine oxidase inhibitors[J]. Med Chem, 2020, 16(1): 119-127.
[23] SUN M, ZHAO J, MAO Q, et al.Synthesis and biological evaluation of 2-(4-alkoxy-3-cyano)phenylpyrimidine derivatives with 4-amino or 4-hydroxy as a pharmacophore element binding with xanthine oxidase active site[J]. Bioorg Med Chem, 2021, 38: 116117.
[24] GAO J, ZHANG Z, ZHANG B, et al.Novel 3-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones as promising xanthine oxidase inhibitors: Design, synthesis and biological evaluation[J]. Bioorg Chem, 2020, 95: 103564.
[25] AGBADUA OG, KÚSZ N, BERKECZ R, et al. Oxidized resveratrol metabolites as potent antioxidants and xanthine oxidase inhibitors[J]. Antioxidants (Basel), 2022, 11(9): 1832.
[26] CHEN JS, WANG MX, WANG MM, et al.Synthesis and biological evaluation of geniposide derivatives as inhibitors of hyperuricemia, inflammatory and fibrosis[J]. Eur J Med Chem, 2022, 237: 114379.
[27] ZHAO J, MAO Q, LIN F, et al.Intramolecular hydrogen bond interruption and scaffold hopping of TMC-5 led to 2-(4-alkoxy-3-cyanophenyl)pyrimidine-4/5-carboxylic acids and 6-(4-alkoxy-3-cyanophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-ones as potent pyrimidine-based xanthine oxidase inhibitors[J]. Eur J Med Chem, 2022, 229: 114086.
[28] ERA B, DELOGU GL, PINTUS F, et al.Looking for new xanthine oxidase inhibitors: 3-Phenylcoumarins versus 2-phenylbenzofurans[J]. Int J Biol Macromol, 2020, 162: 774-780.
[29] ZHANG B, DUAN Y, YANG Y, et al.Design, synthesis, and biological evaluation of N-(3-cyano-1H-indol-5/6-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamides and 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles as novel xanthine oxidase inhibitors[J]. Eur J Med Chem, 2022, 227: 113928.
[30] ZHANG L, WANG S, YANG M, et al.Design, synthesis and bioevaluation of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide derivatives as novel xanthine oxidase inhibitors[J]. Bioorg Med Chem, 2019, 27(9): 1818-1823.
[31] JOSHI G, SHARMA M, KALRA S, et al.Design, synthesis, biological evaluation of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehydes as non-purine xanthine oxidase inhibitors: Tracing the anticancer mechanism via xanthine oxidase inhibition[J]. Bioorg Chem, 2021, 107: 104620.
[32] MALIK N, DHIMAN P, KHATKAR A.In silico design and synthesis of hesperitin derivatives as new xanthine oxidase inhibitors[J]. BMC Chem, 2019, 13(1): 53.
[33] HO SL, LIN CT, LEE SS.In silico design and synthesis of N-arylalkanyl 2-naphthamides as a new class of non-purine xanthine oxidase inhibitors[J]. Drug Dev Res, 2021, 82(6): 789-801.
[34] MARAHATHA R, BASNET S, BHATTARAI BR, et al.Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis[J]. BMC Complement Med Ther, 2021, 21(1): 1.
[35] HU SS, ZHANG TJ, WAND ZR, et al.Design, synthesis and structure-activity relationship of N-phenyl aromatic amide derivatives as novel xanthine oxidase inhibitors[J]. Bioorg Chem, 2023, 133: 106403.
[36] HOSOYA T, SASAKI T, HASHIMOTO H, et al.Clinical efficacy and safety of topiroxostat in Japanese male hyperuricemic patients with or without gout: an exploratory, phase 2a, multicentre, randomized, double-blind, placebo-controlled study[J]. Journal of Clinical Pharmacy and Therapeutics, 2016, 41(3): 298-305.
[37] MACKENZIE IS, FORD I, NUKI G, et al.Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial[J]. Lancet, 2020, 396(10264): 1745-1757.