Discovery of novel 1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors with hypouricemic effects.

Xanthine oxidoreductase (XOR) is a clinically validated target for the treatment of hyperuricemia and gout. A series of novel 1,2,4-triazoles were identified as potent XO inhibitors via a fused-pharmacophore strategy based on the interaction modes of febuxostat and topiroxostat. Among them, compound 7i showed an IC50 value of 0.20 nM against XOR, which was superior to febuxostat and topiroxostat. Furthermore, 7i exhibited significant hypouricemic and serum XOR inhibitory effects in potassium oxonate induced hyperuricemia mouse models. A single-dose toxicity assessment of 7i showed no noticeable toxicity at the dose of 50 mg/kg. These results demonstrated that 7i could be a promising lead compound for the treatment of hyperuricemia and gout.

A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial.

Background: Diabetic kidney disease (DKD) is characterized by albuminuria and reduced renal function. Whether xanthine oxidoreductase inhibitors (XORIs) have a renoprotective effect in DKD patients with type 2 diabetes remains controversial. We conducted a proof-of-concept study to investigate the renal effects of a novel XORI, TMX-049, in patients with DKD and type 2 diabetes. Methods: This is a multicenter, 12-week, randomized, double-blind, placebo-controlled phase 2a trial conducted at 49 centers across the United States between April 2018 and June 2019. In total, 130 patients with type 2 diabetes, urine albumin-creatinine ratio (UACR) 200 - 3000 mg/g, eGFR ≥30 ml/min per 1.73 m2, and serum uric acid (sUA) 4 - 10 mg/dl were randomized 1:1:1 to TMX-049 200 mg (n=44) or 40 mg (n=44), or placebo (n=42). The primary end point was change in log-transformed UACR at week 12 from baseline. The secondary end points included changes in UACR, eGFR, and sUA from baseline. Results: The least squares mean differences for changes in log-transformed UACR from baseline to week 12 compared with placebo were -0.43 (95% confidence interval [95% CI], -0.82 to -0.04, P=0.03) for TMX-049 200 mg and -0.05 (95% CI, -0.44 to 0.34, P=0.80) for 40 mg; a 35% reduction in UACR was observed with TMX-049 200 mg (ratio versus placebo, 0.65; 95% CI, 0.44 to 0.96) but not 40 mg (0.95; 95% CI, 0.64 to 1.41). Throughout the treatment period, marked reductions in sUA levels but no changes in eGFR were observed with both TMX-049 doses. TMX-049 was generally well tolerated, although two patients with TMX-049 200 mg developed gout. Conclusions: TMX-049 200 mg reduced albuminuria at 12 weeks in patients with DKD and type 2 diabetes. TMX-049 may exert a renoprotective effect independent of its sUA-lowering effect.

"Repurposing" of Xanthine Oxidoreductase as a Nitrite Reductase: A New Paradigm for Therapeutic Targeting in Hypertension.

SIGNIFICANCE: In contrast to nitric oxide (NO), which has well-established, important effects in regulation of cardiovascular homeostasis, its oxidative metabolite nitrite has, until recently, been considered to be of minor functional significance. RECENT ADVANCES: However, this view of nitrite has been radically revised over the past 10 years with evidence now supporting a critical role for this anion as a storage form of NO. CRITICAL ISSUES: Importantly, while hypoxia and acidosis have been shown to play a pivotal role in the generation of nitrite to NO, a number of mammalian nitrite reductases have been identified that facilitate the reduction of nitrite. Critically, these nitrite reductases have been demonstrated to operate under physiological pH conditions and in normoxia, extending the functional remit of this anion from an ischemic mediator to an important regulator of physiology. One particular nitrite reductase that has been shown to operate under a wide range of environmental conditions is the enzyme xanthine oxidoreductase (XOR). FUTURE DIRECTIONS: In this review, we discuss the evidence supporting a role for XOR as a nitrite reductase while focusing particularly on its function in hypertension. In addition, we discuss the potential merit in exploiting this activity of XOR in the therapeutics of hypertension.