Zurampic (lesinurad) / AstraZeneca - LARVOL DELTA

Decoding gout pathogenesis: target discovery and drug design through computational models. (PubMed, In Silico Pharmacol) - "Molecular docking by AutoDock Vina and AutoDock4 of whole Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT) database, Food and Drug Administration (FDA) Approved Drugs revealed three leads from the Woodfordia fruticosa (Heterophylliin A), Arctium lappa (Arctignan D), and Oroxylum indicum (Scutellarein 7-rutinoside) demonstrated strong binding affinities with URAT1 through favorable docking interactions over the best docked Fostemsavir and URAT1 inhibitors (Lesinurad and Benzbromarone) indicating their potential as modulators of uric acid transport. This integrative bioinformatics and computational approach provide a robust framework for discovering potent drug target and bioactive compounds with strong potential for effective gout treatment if further validated through in vitro and in vivo assays. The online version contains supplementary material available at 10.1007/s40203-025-00476-5."

Journal • Gout • Immunology • Inflammatory Arthritis • Rheumatology

Incidence and risk of nephrolithiasis with uricosuric therapies for the treatment of gout: a systematic review and meta-analysis of randomised controlled trials and cohort studies. (PubMed, Rheumatology (Oxford)) - "Nephrolithiasis is a common side-effect of uricosuric therapies, although the quality of evidence for this is low-moderate due to significant heterogeneity and bias. Further research is required to identify those at highest risk, and who may benefit from additional interventions such as urinary alkalinisation. Our estimates of incidence of nephrolithiasis and associated risk can lead to more informed shared treatment decisions in the management of gout."

Journal • Retrospective data • Gout • Inflammatory Arthritis • Nephrology • Renal Calculi • Rheumatology

Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization. (PubMed, Nat Commun) - "Through systematic screening, 32 emerges as a drug candidate, demonstrating potent uric acid-lowering activity in male hyperuricemia mouse models (efficacy comparable to febuxostat and superior to lesinurad and benzbromarone) by inhibiting key urate transporters. Notably, 32 exhibits enhanced safety compared to control drugs. This study exemplifies a natural product-inspired, dual-mechanism drug discovery approach, showcasing the potential of a rational polypharmacology and thus offering therapeutic opportunities for gout management."

Journal • Preclinical • Gout • Immunology • Inflammation • Inflammatory Arthritis • Rheumatology

Serum uric acid, renal status, cardiovascular-kidney-metabolic syndrome and drug therapy, a wide-angled Mendelian randomization analysis. (PubMed, Am Heart J Plus) - "Lesinurad targeting SLC22A11 and SLC22A12 was validated for treating IHD. Our study clarified the complex relationship among SUA, renal status and CKM syndrome. Simultaneously providing innovative drug and social interventions for CKM syndrome."

Journal • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Coronary Artery Disease • Depression • Diabetes • Heart Failure • Hypertension • Metabolic Disorders • Nephrology • Obstructive Sleep Apnea • Peripheral Arterial Disease • Psychiatry • Renal Disease • Respiratory Diseases • Sleep Apnea • Sleep Disorder • Vascular Neurology • CRP

Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects. (PubMed, Bioorg Med Chem Lett) - "Most compounds potently inhibit the human URAT1 in HEK293 cells, and the most active compound 7 exhibited an IC50 of 0.72 μM, which was much more potent than Lesinurad and comparable to Benzbromarone...The urate-lowering effects of compounds 1 and 7 were confirmed in two different hyperuricemia mouse models, and no obvious toxicity was observed in the treated mice. The results provide new chemical prototypes for urate-lowering drug discovery targeting URAT1."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Molecular mechanism of drug inhibition of URAT1. (PubMed, Nat Commun) - "Here, we present structures of the double-mutant rat homolog of URAT1 in complex with its substrate urate, and the clinical drugs benzbromarone, lesinurad, verinurad, and sulfinpyrazone. Additionally, critical interactions essential for its conformational transition are identified. These findings provide a molecular framework for understanding the physiological function of URAT1 and for developing more efficacious therapies to treat hyperuricemia."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Discovery and Optimization of 6‑Azaindole URAT1 Inhibitors to Address Kidney and Liver Related Toxicities. (PubMed, ACS Med Chem Lett) - "However, existing URAT1 inhibitors such as lesinurad and benzbromarone present significant kidney and liver toxicity risks, respectively...Additionally, 22k exhibited no glutathione (GSH) trapping, unlike benzbromarone, indicating reduced risk of reactive metabolites formation and a lower potential for idiosyncratic liver toxicity. These findings highlight 22k as a promising next-generation URAT1 inhibitor with improved safety profile, warranting further investigations."

Journal • Gout • Inflammatory Arthritis • Metabolic Disorders • Rheumatology

GAPS IN CHRONIC AND ACUTE GOUT CARE: REAL-WORLD DATA FROM AN ELECTRONIC HEALTH RECORD-BASED REGISTER (EULAR 2025) - "Use of urate-lowering therapy (ULT)—allopurinol, febuxostat, probenecid, lesinurad, or rasburicase—was evaluated during the in- or outpatient encounter where tophi were documented, as well as at previous and subsequent visits...Use of anti-inflammatory drugs (NSAIDs, colchicine, IL-1 inhibitor, or glucocorticoids) was assessed during hospitalization or within ±2 weeks of a joint aspiration or flare documentation... The prescription of ULT in patients with tophus is suboptimal. Furthermore, a significant proportion of patients who were previously treated did not receive ongoing therapy. Many patients with acute gout flares do not receive anti-inflammatory treatment, potentially resulting in prolonged pain, extended hospital stays, and the risk of major adverse cardiac event."

Clinical • Real-world • Real-world evidence • Gout • Inflammatory Arthritis • Pain • Rheumatology

Molecular basis of the urate transporter URAT1 inhibition by gout drugs. (PubMed, Nat Commun) - "Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the recently developed compound TD-3...Furthermore, we discover differences in the inhibitor-dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia."

Journal • Gout • Inflammation • Inflammatory Arthritis • Pain • Rheumatology

Development of a fluorescence-based assay for screening of urate transporter 1 inhibitors (II): Optimization of fluorescent substrates and structure-activity relationships analysis. (PubMed, J Pharm Biomed Anal) - "Using DBF or DIF as substrates, the IC50 values of the URAT1 inhibitors benzbromarone and lesinurad remained within the same order of magnitude as those obtained by 6-CFL...Molecular dynamics (MD) simulations and free energy calculations were employed to compare the interactions and binding affinities of 6-CFL, DBF, and DIF with URAT1, respectively. Finally, structure-activity relationships (SARs) analysis was conducted to preliminarily identify substituents modulating the binding affinity of commercially available fluoresceins."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Simultaneous determination of lesinurad and co-administered drugs used in management of gout comorbidities to uncover potential pharmacokinetic interaction in rat plasma. (PubMed, Sci Rep) - "This work presents a novel, simple, and sensitive high performance liquid chromatography (HPLC) method for the simultaneous determination of lesinurad (LES) and other co-administered drugs that are subject to potential pharmacokinetic interactions such as etoricoxib (ETC), eplerenone (EPL), and amiodarone (AMD) in rat plasma. This raises concerns of the possible renal injurious effect of ETC when co-prescribed with LES. Moreover, this work uncovers the necessity for therapeutic dose adjustment or increased clinical vigilance for side effects and/or lack of efficacy upon concomitant administration of the selected drugs to gout patients."

Journal • PK/PD data • Preclinical • Gout • Immunology • Inflammatory Arthritis • Rheumatology

Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs. (PubMed, Cell Discov) - "Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of urate transport and anti-gout medication action and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout."

Journal • Gout • Inflammatory Arthritis • Pain • Rheumatology

Are participants in gout medication registration clinical trials representative of people with gout in the general population? (PubMed, Semin Arthritis Rheum) - "FDA approved gout medication trials since 2009 have not enrolled a study population that is representative of the US general population with gout, particularly regarding age, ethnicity, and cardiometabolic comorbidities. For broader applicability, future phase 3 trials should ensure the greater inclusion of women, older individuals, diverse ethnicities, and those with common gout-associated comorbid conditions."

Journal • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Gout • Heart Failure • Hypertension • Inflammatory Arthritis • Metabolic Disorders • Myocardial Infarction • Nephrology • Renal Calculi • Renal Disease • Rheumatology

Luciferase-based bioluminescence revealed the facilitated diffusion of D-luciferin mediated by SLC17A3. (PubMed, Biochem Biophys Res Commun) - "Interestingly, we found that sulfinpyrazone and lesinurad, uricosuric drugs that inhibit SLC22A12/URAT1, are potent SLC17A3 inhibitors, suggesting the possibility that they alter the pharmacokinetics of OAT1/OAT3-substrate drugs and urate...This strategy enables the study of its transport activity and the identification of potential SLC17A3-mediated drug-drug interactions. This approach also provides an opportunity to elucidate the molecular mechanisms involved in the urinary excretion of organic anions."

Journal

Discovery of cyanidin-3-O-galactoside as a novel CNT2 inhibitor for the treatment of hyperuricemia. (PubMed, Bioorg Chem) - "The serum CR and BUN levels indicate that Cy3Gal does not exhibit any apparent renal toxicity compared to lesinurad and allopurinol. HE examination showed no noticeable pathological changes in the kidneys or colons after treatment with Cy3Gal. In summary, Cy3Gal could be a CNT2 inhibitor with favorable drugability for the treatment of hyperuricemia."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Are Participants in Gout Clinical Trials Representative of People with Gout in the General Population? (ACR Convergence 2024) - "The approved gout medications were febuxostat, colchicine, pegloticase, lesinurad, and canakinumab. Clinical trials of gout medications approved by the FDA since 2009 have not enrolled a study population that is representative of the US population with gout, based on demographic features and cardiometabolic comorbidities. For broader applicability to the general population with gout, future phase 3 trials should ensure representative inclusion of women, older individuals, diverse ethnicities, and those with comorbid health conditions that are commonly experienced by people with gout."

Clinical • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Gout • Heart Failure • Hypertension • Inflammatory Arthritis • Metabolic Disorders • Myocardial Infarction • Nephrology • Renal Calculi • Renal Disease • Rheumatology

Molecular basis of the urate transporter URAT1 inhibition by gout drugs. (PubMed, bioRxiv) - "Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the novel compound TD-3...Furthermore, we discover differences in the inhibitor dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia."

Journal • Gout • Inflammation • Inflammatory Arthritis • Pain • Rheumatology

Transport mechanism and structural pharmacology of human urate transporter URAT1. (PubMed, Cell Res) - "To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics."

Journal • Gout • Immunology • Inflammatory Arthritis • Pain • Rheumatology

Design, synthesis and bioactivity evaluation of isobavachin derivatives as hURAT1 inhibitors for hyperuricemia agents. (PubMed, Eur J Med Chem) - "Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent."

Journal

Evaluation of the inhibitory effects of antigout drugs on human carboxylesterases in vitro. (PubMed, Toxicol In Vitro) - "The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice."

Journal • Preclinical • Cardiovascular • Chronic Kidney Disease • Gout • Inflammatory Arthritis • Metabolic Disorders • Nephrology • Renal Disease • Rheumatology

Discovery of digallic acid as XOD/URAT1 dual target inhibitor for the treatment of hyperuricemia. (PubMed, Bioorg Chem) - "Digallic acid inhibited URAT1 with an IC50 of 5.34 ± 0.65 μM, which is less potent than benzbromarone (2.01 ± 0.36 μM) but more potent than lesinurad (10.36 ± 1.23 μM)...Further toxicity evaluation indicated that digallic acid exhibited no obvious renal toxicity, as reflected by CCK-8, biochemical analysis (CR and BUN) and HE examination. The findings of our study can provide valuable insights for the development of XOD/URAT1 dual target inhibitors, and digallic acid deserves further investigation as a potential anti-hyperuricemic drug."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Virtual screening and biological evaluation of natural products as urate transporter 1 (URAT1) inhibitors. (PubMed, J Biomol Struct Dyn) - "After molecular docking and conformational evaluation, four e-pharmacophoric models were constructed based on the complex structures of probenecid-URAT1, benzbromarone-URAT1, lesinurad-URAT1, and verinurad-URAT1. The results showed that the carbonyl group on C-4 and hydroxyl group on C-7, C-4', and C-5' in flavonoids were conducive for URAT1 inhibitory effects. This study facilitates the application of flavonoids in the development of URAT1 inhibitors.Communicated by Ramaswamy H. Sarma."

Journal

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities. (PubMed, Eur J Med Chem) - "Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad...Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Nephrolithiasis associated with uricosuric therapies for the treatment of gout: a systematic review (BSR 2024) - "Ten studies assessed Benzbromarone monotherapy, five Lesinurad plus xanthine oxidase inhibitor (XOI), four Probenecid, three Sulfinpyrazone and one Lesinurad monotherapy (total 3091 participants). Nephrolithiasis is a common side-effect of uricosuric therapy for gout. Future studies should provide risk estimates between uricosuric-treated and untreated groups, describe clinical presentation of stone events and, where possible, assess stone composition."

Review • Gout • Inflammatory Arthritis • Nephrology • Renal Calculi • Rheumatology

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability. (PubMed, J Med Chem) - "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...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."

Journal • Gout • Inflammatory Arthritis • Metabolic Disorders • Rheumatology