Some quinoline containing c-Met kinase inhibitors are aldehyde oxidase (AO) substrates. 3-substituted quinoline triazolopyridine analogues were synthesized to understand the electron donating and steric hindrance effect on AO-mediated metabolism. Metabolic stability studies for these quinoline analogues were carried out in liver cytosol from mice, rats, cyno monkeys, and humans. Several 3-N-substituted analogues were found to be unstable in monkey liver cytosolic incubations (t1/2 < 10 min), and five of them (63, 53, 51, 11, and 71) were chosen for additional mechanistic studies. Monooxygenation on the quinoline ring was identified by LC/MS/MS. Metabolite formation was inhibited by the AO inhibitors menadione and raloxifene, but not by the xanthine oxidase inhibitor allopurinol. It was found that small electron donating groups at the 3-quinoline moiety made the analogues more susceptible to AO metabolism, while large 3-substituents could reverse the trend. Although species differences were observed, this trend was applicable to all species tested. Small electron donating substituents at the 3-quinoline moiety increased both affinity (decreased Km) and Vmax towards AO in kinetic studies, while large substituents decreased both parameters probably due to steric hindrance. Based on our analysis, a common structural feature with high AO liability was proposed. Our finding could provide useful information for chemists to minimize potential AO liability when designing quinoline analogues.

The aim of this research work was to observe and analyze the efficacy of febuxostat and allopurinol in the treatment of gout with hyperuricemia. The 160 patients who has been diagnosed with gout and hyperuricemia in our hospital were selected as research objects. They were randomly divided into research group and control group, each containing 80. The control group received conventional allopurinol treatment, while the research group was treated with febuxostat. Then, the treatment efficacy was compared between the two groups. Through comparison of blood uric acid levels between the two groups after treatment, it can be known that improvement was more significant in the research group, P<0.05. The adverse reaction rate in the research group was significantly lower, P<0.05. For patients with gout and hyperuricemia, febuxostat therapy has better efficacy than that of allopurinol.

HLA-B*58:01 has been demonstrated to be associated with allopurinol-induced severe cutaneous adverse reactions. Since HLA-B*58:01 is too complicated to be identified, it is necessary to select an appropriate surrogate biomarker. In Japan, the rs9263726 allele was considered as a surrogate biomarker for HLA-B*58:01, but this was not the case with the Australian cohort. Due to the conflict results, in this study, we aim to demonstrate whether the rs9263726 allele is a surrogate biomarker for HLA-B*58:01 in Han Chinese population. A total of 353 samples (200 cases from the south and 153 cases from the north) were selected to detect HLA-B*58:01 and rs9263726 allele. The HLA-B*58:01 was identified by sequencing-based method, and the rs9263726 allele was identified by Taqman SNP Genotyping Assays. The results showed that the two alleles had a linkage, but not absolute linkage disequilibrium in Han Chinese population.

Xanthine oxidase (XO) is an interesting target for the synergic treatment of several diseases. Coumarin scaffold plays an important role in the design of efficient and potent inhibitors. In the current work, twenty 3-arylcoumarins and eight 3-heteroarylcoumarins were evaluated for their ability to inhibit XO. Among all the candidates, 5,7-dihydroxy-3-(3'-hydroxyphenyl)coumarin (compound 20) proved to be the best inhibitor with an IC50 of 2.13 μM, being 7-fold better than the reference compound, allopurinol (IC50 = 14.75 μM). To deeply understand the potential of this compound, the inhibition mode was also evaluated. Compound 20 showed an uncompetitive profile of inhibition. Molecular docking studies were carried out to analyze the interaction of compound 20 with the studied enzyme. The binding mode involving residues different from the catalytic site of the binding pocket, is compatible to the observed uncompetitive inhibition. Compound 20 was not cytotoxic at its IC50 value, as demonstrated by the viability of 99.1% in 3 T3 cells. Furthermore, pharmacokinetics and physicochemical properties were also calculated, which corroborated with the potential of the studied compounds as promising XO inhibitors.

Febuxostat is potent and well-tolerated in the management of chronic gout. However, its clinical efficacy and safety in the treatment of hyperuricemia in patients with chronic kidney disease (CKD) and in renal transplant recipients have remained to be fully determined. The MEDLINE, EMBASE and Cochrane Library databases were searched for relevant articles. Data were extracted and pooled results were estimated from the standard mean difference (SMD) with 95% confidence intervals (95% CIs). The quality of the studies included was assessed, and their publication bias was examined. Four prospective randomized controlled trials and two retrospective observational studies were included in the systematic review and meta-analysis. Febuxostat administration significantly reduced the serum uric acid concentration in patients with CKD and in renal transplant recipients when compared with allopurinol or placebo in the short-term (1 month: SMD, -2.24; 95% CI, -3.59 to -0.89; P-value of SMD=0.001; I2, 92.4%; 3 months: SMD, -1.20; 95% CI, -2.04 to -0.36; P-value of SMD=0.005; I2, 88.9%; 6 months: SMD, -1.49; 95% CI, -2.68 to -0.30; P-value of SMD=0.014; I2, 92.9%). Furthermore, the increase in the estimated glomerular filtration rate in the febuxostat group was significantly higher than that in the control group (SMD, 0.30; 95% CI, 0.031 to 0.58; P-value of SMD=0.029; I2, 0.0%). No significant difference in the changes in serum creatinine (Scr), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) was identified between the two groups (Scr: SMD, -0.17; 95% CI, -0.97 to 0.63; P-value of SMD=0.67; I2, 79.2%; LDL: SMD, -0.21; 95% CI, -0.49 to 0.07; P-value of SMD=0.13; I2, 34.1%; HDL: SMD, -0.05; 95% CI, -0.70 to 0.61; P-value of SMD=0.89; I2, 69.2%). In conclusion, febuxostat is a potent and well-tolerated agent for the short-term management of hyperuricemia in patients with CKD and in renal transplant recipients. However, these data should be interpreted with caution due to the varied design of the studies included in the present meta-analysis.