Design, synthesis and activity evaluation of novel lesinurad analogues containing thienopyrimidinone or pyridine substructure as human urate transporter 1 inhibitors

Zhang, Jian; Dong, Yue; Gao, Shenghua; Zhang, Xujie; Liao, Hui; Shi, Xiaoyu; Zhang, Zhijiao; Zhao, Tong; Liang, Ruipeng; Qi, Danhui; Wu, Ting; Pang, Jianxin; Liu, Xinyong; Zhan, Peng

doi:10.1016/j.ejmech.2022.114816

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…However, compared with that of 36a, the inhibitory activities of compounds (40) on URAT1 did not increase. 78 Among them, compound 40a exhibited the highest inhibitory activity (IC 50 = 7.56 ± 0.52 μM).…”

Section: Agents Promoting Ua Excretionmentioning

confidence: 99%

“…Accordingly, they devised a series of compounds (40) by hybridizing the core region of AW-3 with the modified part C of compound 36a while retaining the cyclopropyl naphthalene moiety. However, compared with that of 36a , the inhibitory activities of compounds (40) on URAT1 did not increase . Among them, compound 40a exhibited the highest inhibitory activity (IC 50 = 7.56 ± 0.52 μM).…”

Section: Agents Promoting Ua Excretionmentioning

confidence: 99%

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Agents for the Treatment of Gout: Current Advances and Future Perspectives

Zeng,

Liu,

Fan

et al. 2023

J. Med. Chem.

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Gout is characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals around joints. Despite the availability of several drugs on the market, its treatment remains challenging owing to the notable side effects, such as hepatorenal toxicity and cardiovascular complications, that are associated with most existing agents. This perspective aims to summarize the current research progress in the development of antigout agents, particularly focusing on xanthine oxidase (XO) and urate anion transporter 1 (URAT1) inhibitors from a medicinal chemistry viewpoint and their preliminary structure–activity relationships (SARs). This perspective provides valuable insights and theoretical guidance to medicinal chemists for the discovery of antigout agents with novel chemical structures, better efficiency, and lower toxicity.

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Section: Agents Promoting Ua Excretionmentioning

confidence: 99%

Section: Agents Promoting Ua Excretionmentioning

confidence: 99%

Agents for the Treatment of Gout: Current Advances and Future Perspectives

Zeng,

Liu,

Fan

et al. 2023

J. Med. Chem.

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“…Development of novel URAT1 inhibitors. (a) Structures and bioactivities of T7 and TD-3 reported in our previous work. − (b) Structure, bioactivities, and predicted binding mode of lesinurad (green, picture was generated by Schrödinger suite 2023-1 and Pymol), and general formula of newly designed target compounds in this study.…”

Section: Introductionmentioning

confidence: 99%

“…Ultimately, several drug candidates were obtained, including T7 and TD-3 which exhibited significant SUA-lowering activity in vivo , as well as inhibitory effects on URAT1 in vitro while possessing favorable drug-like properties and safety profiles (Figure ). − …”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

Shi,

Zhao,

Wang

et al. 2024

J. Med. Chem.

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Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC 50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC 50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

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