Overview of the pharmacokinetics and pharmacodynamics of URAT1 inhibitors for the treatment of hyperuricemia and gout

Hou, Zihan; Ma, Aijinxiu; Mao, Jiale; Song, Danni; Zhao, Xu

doi:10.1080/17425255.2023.2287477

Cited by 3 publications

(1 citation statement)

References 109 publications

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“…The unavailability of structural information for URAT1 has led our previous study to primarily focus on the ligand-based discovery of novel URAT1 inhibitors through iterative exploration of the chemical space surrounding lesinurad. 24 The representative URAT1 inhibitors (as exemplified by lesinurad) comprise three primary structural components: a core heterocyclic ring (referred to as component A), a hydrophobic feature (known as component B), and an anionic group (designated as component C). The substitution of the brominated triazole moiety was carried out using 1Himidazole [4,5-b]pyridine, and a methylene group was introduced as a linker to eliminate chirality.…”

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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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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Identification of aurones and chalcones as the main contributors to xanthine oxidase inhibitory activity of snow chrysanthemum

Xiao,

Wang,

Sun

et al. 2024

Food Bioscience

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Comprehensive Screening and Evaluation of Anti-gout Activity of Plantago asiatica L. through Integrated In vivo and In vitro Methodologies

Gao,

Liu,

Hou

et al. 2024

World Journal of Traditional Chinese Medicine

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Objective: This study aimed to elucidate the active components and mechanisms of Plantago asiatica L. (PAL) in the treatment of gout. Materials and Methods: Based on its polarity, PAL was partitioned into three parts, P1, P2, and P3, through gradient elution using AB-8 macroporous resin columns. The primary constituents of these fractions include iridoids, phenylethanoid glucosides, and flavonoids. Subsequently, a comprehensive in vitro and in vivo screening and evaluation model was developed considering the fundamental pathological processes of gout, including the inhibition of uric acid (UA) production, augmentation of UA excretion, and anti-inflammatory effects. This model was used to analyze the anti-gout activity of P1, P2, P3, and the overall extracts derived from PAL. Results: All the PAL parts exhibited specific therapeutic properties as part of gout therapy. Specifically, the P2 part demonstrated the ability to diminish interleukin-1 beta levels, lower UA concentrations, suppress joint inflammation in rats, and restore abnormal parameters associated with gout, such as creatinine and urea nitrogen. These findings highlight the significant effect of P2 on gout treatment. Conclusions: Following a thorough assessment of the outcomes derived from diverse anti-gout experiments, P2 exhibited superior anti-gout properties compared to the remaining parts. P2 demonstrated a restorative effect on the aberrant parameters associated with gout, thereby comprehensively elucidating the therapeutic mechanism of P2 against gout. This study provides substantial evidence and serves as a reference for future investigations regarding the material foundation of PAL in gout treatment.

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Overview of the pharmacokinetics and pharmacodynamics of URAT1 inhibitors for the treatment of hyperuricemia and gout

Cited by 3 publications

References 109 publications

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

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

Identification of aurones and chalcones as the main contributors to xanthine oxidase inhibitory activity of snow chrysanthemum

Comprehensive Screening and Evaluation of Anti-gout Activity of Plantago asiatica L. through Integrated In vivo and In vitro Methodologies

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