Synthesis and Biological Evaluation of Novel Aryl-2&lt;i&gt;H&lt;/i&gt;-pyrazole Derivatives as Potent Non-purine Xanthine Oxidase Inhibitors

Sun, Zhi-Gang; Zhou, Xiaojing; Zhu, Maguang; Ding, Wen-Ze; Li, Zhen; Zhu, Hai‐Liang

doi:10.1248/cpb.c15-00282

Cited by 10 publications

(2 citation statements)

References 17 publications

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“…Sun et al used ad ihydropyrazole ring as linker between three aromatic systems 169. [121] The highest inhibition was obtainedw ith compound 170,p ossessing an IC 50 value of 9.8 mm,s imilart ot hat of allopurinol (IC 50 of 9.5 mm). Interestingly,t he activity was drastically decreased if there was only one methoxy group in the meta position.…”

Section: Zhang Et Al In 2017mentioning

confidence: 86%

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

2019

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Xanthine oxidase (XO) is the enzyme responsible for the catabolism of purines and their conversion into uric acid. XO is thus the target for the treatment of hyperuricemia and gout. For more than 50 years the only XO inhibitor drug available on the market was the purine analogue allopurinol. In the last decade there has been a resurgence in the search for new inhibitors of XO, as the activity of XO and hyperuricemia have also been associated with a variety of conditions such as diabetes, hypertension, and other cardiovascular diseases. In recent years the non‐purine inhibitor febuxostat was approved in Europe and the USA for the treatment of hyperuricemia. This drug was followed by another XO inhibitor called topiroxostat. This review discusses the molecular structures and activities of the multiple classes of inhibitors that have been developed since the discovery of allopurinol, with a brief review of the molecular interactions between inhibitors and XO active site residues for the most important molecules. The challenges ahead for the discovery of new inhibitors of XO with novel chemical structures are discussed.

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Section: Zhang Et Al In 2017mentioning

confidence: 86%

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

2019

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“…Thus, there is an urgent need to develop new XOR inhibitors with no or milder adverse effects. In recent years, several synthesized purine analogs were reported to have XOR inhibitory effects: 9-benzoyl 9-deazaguanines [ 94 ], N-(1,3-diaryl-3-oxopropyl)amides [ 95 ] and 5,6-dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives [ 96 ] and naphthopyrans [ 97 ]; non-purine analogs such as thiadiazolopyrimidin-5-ones [ 98 ], aryl-2H-pyrazole derivatives [ 99 ], 2-amino-5-alkylidene-thiazol-4-ones [ 100 ], and others [ 101 , 102 ]; and natural or natural derivatives such as riparsaponin [ 103 ], genistein [ 104 ], morin [ 105 ], curcumin analogs [ 106 ], and others [ 107 – 109 ] ( Table 1 ). Recently, we have focused on the natural derivatives for the development of novel XOR inhibitors [ 109 ], which could be possible alternatives for allopurinol and febuxostat, or at least in combination therapy to minimize the adverse effects of current drugs, in particular in long-term applications for symptomatic and asymptomatic hyperuricemia-related diseases.…”

Section: Development Of New Xor Inhibitorsmentioning

confidence: 99%

Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview

2016

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Uric acid is the final oxidation product of purine metabolism in humans. Xanthine oxidoreductase (XOR) catalyzes oxidative hydroxylation of hypoxanthine to xanthine to uric acid, accompanying the production of reactive oxygen species (ROS). Uric acid usually forms ions and salts known as urates and acid urates in serum. Clinically, overproduction or under-excretion of uric acid results in the elevated level of serum uric acid (SUA), termed hyperuricemia, which has long been established as the major etiologic factor in gout. Accordingly, urate-lowering drugs such as allopurinol, an XOR-inhibitor, are extensively used for the treatment of gout. In recent years, the prevalence of hyperuricemia has significantly increased and more clinical investigations have confirmed that hyperuricemia is an independent risk factor for cardiovascular disease, hypertension, diabetes, and many other diseases. Urate-lowering therapy may also play a critical role in the management of these diseases. However, current XOR-inhibitor drugs such as allopurinol and febuxostat may have significant adverse effects. Therefore, there has been great effort to develop new XOR-inhibitor drugs with less or no toxicity for the long-term treatment or prevention of these hyperuricemia-related diseases. In this review, we discuss the mechanism of uric acid homeostasis and alterations, updated prevalence, therapeutic outcomes, and molecular pathophysiology of hyperuricemia-related diseases. We also summarize current discoveries in the development of new XOR inhibitors.

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Natural potential neuroinflammatory inhibitors from Alhagi sparsifolia Shap.

Zhou

Wei

Jiang

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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Synthesis and Biological Evaluation of Novel Aryl-2<i>H</i>-pyrazole Derivatives as Potent Non-purine Xanthine Oxidase Inhibitors

Cited by 10 publications

References 17 publications

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview

Natural potential neuroinflammatory inhibitors from Alhagi sparsifolia Shap.

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