Pathology, target discovery, and the evolution of XO inhibitors from the first discovery to recent advances (2020–2023)

Kumar, Nitish; Kaur, Komalpreet; Kaur, Navjot; Singh, Ekampreet; Bedi, Preet Mohinder Singh

doi:10.1016/j.bioorg.2023.107042

Cited by 4 publications

(1 citation statement)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These medications are commonly prescribed as first-line treatment options. However, it is important to acknowledge that they may also lead to serious adverse effects including allergic responses, diarrhea, and lethargy. − The other group is uricosuric medications including probenecid (c), benzbromarone (d), lesinurad (e), and dotinurad (f), which can be administered either individually or in combination with XOIs . The primary mechanism of action for these medications is the inhibition of URAT1.…”

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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

Effects of WN1703 on Cardiovascular Function in Chronic Hyperuricemia Rats and Myocardial Injury Mechanism Exploration in H9C2 Cells

Lu,

Liu,

Chen

et al. 2024

J of Applied Toxicology

View full text Add to dashboard Cite

Hyperuricemia, a prevalent condition, is typically preceded by disturbances in purine metabolism and is frequently associated with hyperlipidemia and other dysfunctions of metabolism. WN1703 demonstrated an inhibitory activity against xanthine oxidoreductase (XOR) that was comparable to febuxostat in our prior investigation. In this study, we assessed the cardiovascular safety of WN1703 in a chronic hyperuricemia rat model induced by potassium oxonate in combination with hypoxanthine. We investigated the changes in cardiovascular biomarkers in chronic hyperuricemia rats treated with febuxostat and WN1703, including creatine kinase (CK), CK‐MB, B type natriuretic peptide (BNP), Corin protein (CRN), Neprilysin (NEP), myeloperoxidase (MPO), 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG), tumor necrosis factor (TNF‐α), interleukin‐1β (IL‐1β), and interleukin‐8 (IL‐8). Additionally, we validated the potential mechanism of cardiac injury induced by WN1703 in H9C2 cells, guided by cardiotoxicity predictions from the cardioToxCSM database and network pharmacology. We observed that excessively rapid urate‐lowering, oxidative stress, and inflammation could disrupt myocardial functional homeostasis and increase the risk of cardiovascular injury in hyperuricemia rats, and WN1703 treatment effectively reduced the levels oxidative stress marker 8‐OHdG and inflammatory factor TNF‐α. Despite the absence of organic damage to the heart with prolonged treatment of febuxostat and WN1703, potential hazard of cardiovascular injury could be associated with the modulation of the TGFβ and RHO/ROCK signaling pathways by febuxostat and WN1703. This could offer new insights into the mechanisms underlying the adverse effects caused by XOR inhibitors.

show abstract

Exploring the anti-gout potential of sunflower receptacles alkaloids: A computational and pharmacological analysis

Wang,

Cui,

Liu

et al. 2024

Computers in Biology and Medicine

View full text Add to dashboard Cite

Pathology, target discovery, and the evolution of XO inhibitors from the first discovery to recent advances (2020–2023)

Cited by 4 publications

References 107 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

Effects of WN1703 on Cardiovascular Function in Chronic Hyperuricemia Rats and Myocardial Injury Mechanism Exploration in H9C2 Cells

Exploring the anti-gout potential of sunflower receptacles alkaloids: A computational and pharmacological analysis

Contact Info

Product

Resources

About