Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees

Komoriya, Keiji; Osada, Yoshio; Hasegawa, Masaichi; Horiuchi, Hideki; Kondô, Shirô; Couch, Ronald C.; Griffin, Travis B.

doi:10.1016/0014-2999(93)90033-e

Cited by 64 publications

(28 citation statements)

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“…1B) is another recently developed inhibitor of XOR. When tested in rats and chimpanzees, its inhibition of uric acid production in vivo was stronger and lasted longer than that of allopurinol, without causing any noticeable side effects (21,22). The molecular structure of this inhibitor is quite dissimilar to that of substrates like xanthine or hypoxanthine, strongly suggesting that its mode of action will be different from that of allopurinol.…”

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confidence: 99%

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

Okamoto

Eger

Nishino

et al. 2003

Journal of Biological Chemistry

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372

159

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TEI-6720 (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid) is an extremely potent inhibirespectively. Fluorescence-monitored titration experiments showed that TEI-6720 bound very tightly to both the active and the inactive desulfo-form of the enzyme. The dissociation constant determined for the desulfoform was 2 ؎ 0.03 ؋ 10 ؊9 M; for the active form, the corresponding number was too low to allow accurate measurements. The crystal structure of the active sulfoform of milk xanthine dehydrogenase complexed with TEI-6720 and determined at 2.8-Å resolution revealed the inhibitor molecule bound in a long, narrow channel leading to the molybdenum-pterin active site of the enzyme. It filled up most of the channel and the immediate environment of the cofactor, very effectively inhibiting the activity of the enzyme through the prevention of substrate binding. Although the inhibitor did not directly coordinate to the molybdenum ion, numerous hydrogen bonds as well as hydrophobic interactions with the protein matrix were observed, most of which are also used in substrate recognition.

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confidence: 99%

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

Okamoto

Eger

Nishino

et al. 2003

Journal of Biological Chemistry

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372

159

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“…Although oxypurinol binds to XO with high affinity and is a potent inhibitor, the binding and inhibition are reversed over several hours as a result of auto-oxidation of the molybdenum-pterin moiety of the enzyme. Indeed, in animal studies, febuxostat has shown more potent and longer-lasting hypouricemic activity than allopurinol (17)(18)(19). Previous clinical studies have also shown that febuxostat produces significant dose-dependent decreases in sUA levels as a result of inhibition of uric acid production (20).…”

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confidence: 99%

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: A twenty‐eight–day, multicenter, phase II, randomized, double‐blind, placebo‐controlled, dose‐response clinical trial examining safety and efficacy in patients with gout

Becker¹,

Schumacher²,

Wortmann³

et al. 2005

Arthritis & Rheumatism

237

171

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Objective. Gout affects ϳ1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>8.0 mg/dl).Methods. We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28.Results. Greater proportions of febuxostattreated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups.Conclusion. Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.Uric acid is the end product of purine degradation in humans. Hyperuricemia, a serum concentration of urate that exceeds the limit of urate solubility (ϳ7.0 mg/dl), is a common biochemical abnormality (1). Aberrations in any of the multiple mechanisms involved in the production and/or excretion of uric acid may increase serum urate (sUA) concentrations, and persistent hyperuricemia is a marker of monosodium urate (MSU) supersaturation in extracellular fluid (2). As such, hyperuricemia is a necessary (but often not sufficient) risk factor for MSU crystal deposition in tissues, the fundamental pathophysiologic process underlying the clinical manifestations of gout (3). Gout can thus be defined as MSU crystal deposition disease.

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“…It is a selective inhibitor of XO that has been developed for the treatment of hyperuricemia and gout, as it was found to have a potent inhibitory activity for XO/xanthine dehydrogenase (XDH) during evaluation of a range of newly synthesized molecules (Komoriya et al 1993). In humans, the xanthine oxidoreductase (XOR) enzyme catalyzes the last two steps in uric acid synthesis, the oxidation of hypoxanthine to xanthine and of xanthine to uric acid (hypoxanthine → xanthine → uric acid).…”

Section: Pharmacologymentioning

confidence: 99%

“…Febuxostat has numerous hydrogen bonds, salt bridges, and hydrophobic interactions with amino acids in the active site and almost completely fi lls the narrow channel leading to the molybdenum center of the enzyme, which is considered as a structure-based inhibitor, whereas allopurinol and oxypurinol are thought to be mechanism-based inhibitors (Okamoto and Nishino 2008). The XO inhibitory activity and hypouricemic effect of febuxostat compared to allopurinol have been studied in vitro and in a variety of animal models (Komoriya et al 1993;Osada et al 1993;Horiuchi et al 1999). All these studies demonstrated that febuxostat had a greater potency than allopurinol in reducing serum urate levels and/or allantoin levels.…”

Section: Pharmacologymentioning

confidence: 99%

Febuxostat in the management of hyperuricemia and chronic gout: a review

Tomlinson

2008

TCRM

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Abstract:Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insuffi ciency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout fl ares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the fi rst major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and effi cacy is required.

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Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees

Cited by 64 publications

References 5 publications

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: A twenty‐eight–day, multicenter, phase II, randomized, double‐blind, placebo‐controlled, dose‐response clinical trial examining safety and efficacy in patients with gout

Febuxostat in the management of hyperuricemia and chronic gout: a review

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