Zurampic (lesinurad) / AstraZeneca - LARVOL DELTA

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

Comparative risk of gout flares when initiating or escalating various urate-lowering therapy: a systematic review with network meta-analysis. (PubMed, Arthritis Care Res (Hoboken)) - "The relative risk of flares when introducing ULT varies depending on ULT drug and dosing strategy. There was limited data on ULT escalation. Flare prophylaxis with colchicine and rilonacept reduces flare incidence. More research is required on the harms and optimal duration of prophylaxis."

Journal • Retrospective data • Review • Gout • Inflammatory Arthritis • Rheumatology

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies. (PubMed, Semin Arthritis Rheum) - "Uric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys."

Journal • Review

The Stiff Joint: Comparative Evaluation of Monotherapy and Combination Therapy With Urate Lowering Agents in Managing Acute Gout. (PubMed, Cureus) - "Innovative medications are required to enhance gout treatment, especially for individuals with concurrent health conditions. These considerations underscore the importance of reviewing both monotherapy and combination therapy approaches for acute gout treatment."

Combination therapy • Journal • Monotherapy • Review • Cardiovascular • Chronic Kidney Disease • Diabetes • Gout • Hypertension • Immunology • Inflammation • Inflammatory Arthritis • Metabolic Disorders • Nephrology • Pain • Renal Disease • Rheumatology

Urate-Lowering Drugs And Muscle Injury: A Systematic Review and Network Meta-Analysis. (PubMed, J Clin Pharmacol) - "No statistically significant differences were found between placebo and six urate-lowering therapies: allopurinol (risk ratio [RR] 1.05, 95% confidence interval [CI] 0.63-1.73), febuxostat (RR 1.10, 95% CI 0.71-1.70), lesinurad (RR 7.00, 95% CI 0.31-160.36), lesinurad concomitant with allopurinol (RR 0.85, 95% CI 0.34-2.11), lesinurad concomitant with febuxostat (RR 1.97, 95% CI 0.55-7.03), and topiroxostat (RR 0.99, 95% CI 0.37-2.65). No statistically significant differences were found between placebo and six urate-lowering therapies: allopurinol (risk ratio [RR] 1.05, 95% confidence interval [CI] 0.63-1.73), febuxostat (RR 1.10, 95% CI 0.71-1.70), lesinurad (RR 7.00, 95% CI 0.31-160.36), lesinurad concomitant with allopurinol (RR 0.85, 95% CI 0.34-2.11), lesinurad concomitant with febuxostat (RR 1.97, 95% CI 0.55-7.03), and topiroxostat (RR 0.99, 95% CI 0.37-2.65). The findings suggest that there is little need to consider the risk of muscle injury when using..."

Journal • Retrospective data • Review

Preventing gout flares when introducing or escalating urate-lowering therapy: a systematic review and network meta-analysis (ARA 2023) - "When compared to placebo plus prophylaxis, the RR of flares using ULT ranged from 1.08 [95% confidence interval (95% CI) 0.87–1.33] for febuxostat 40 mg plus prophylaxis to 2.65 [95% CI 1.58–4.45] for febuxostat 80 mg plus lesinurad 400 mg plus prophylaxis. The relative risk of gout flares when introducing or escalating ULT varies depending on ULT drug and dosing strategy. Prophylaxis with colchicine and rilonacept reduces flare incidence versus ULT alone. More research is required on the harms and optimal duration of prophylaxis."

Retrospective data • Review • Immunology • Inflammatory Arthritis • Rheumatology

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family. (PubMed, Eur Thyroid J) - "Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology."

Journal • SLC22A2

Uricosuric Agents Affect Plasma and Kidney Concentration of Adefovir via Inhibition of Oat1 and Mrp2 in Rats. (PubMed, Biol Pharm Bull) - "Probenecid and lesinurad increased plasma adefovir concentrations and decreased kidney-to-plasma partition coefficient (Kp) in these rats, presumably by inhibiting Oat1. In contrast, dotinurad, a novel uricosuric agent that selectively inhibits URAT1, had no effect on the plasma and kidney concentrations of adefovir. Therefore, due to the lack of interaction with adefovir, dotinurad is expected to have low drug-drug interaction risk mediated by OAT1, and also by MRP2."

Journal • Preclinical

Design, synthesis and activity evaluation of novel lesinurad analogues containing thienopyrimidinone or pyridine substructure as human urate transporter 1 inhibitors. (PubMed, Eur J Med Chem) - "Meanwhile, the preliminary SARs based on the URAT1 inhibitory activity were discussed in detail, which pointed out the direction for further structural optimization. Overall, the thienopyrimidinone and pyridine are prospective skeletons for the developing novel URAT1 inhibitors with considerable potential for optimization."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Different spectrophotometric methods for simultaneous determination of lesinurad and allopurinol in the new FDA approved pharmaceutical preparation; additional greenness evaluation. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "Furthermore, the greenness of the described methods was assessed using four different tools namely, the national environmental method index, the analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The proposed methods showed more adherence to the greenness characters in comparison to the previously reported HPLC method."

FDA event • Journal • Gout • Inflammatory Arthritis • Rheumatology