Xanthine oxidase (XO) (Ki = 0.6 nM)

With Ki and Ki' values of 0.6 nM and 3.1 nM, respectively, showing inhibition of both the oxidized and reduced forms of xanthine oxidase, Febuxostat exhibits strong mixed-type suppression of the activity of pure bovine milk xanthine oxidase[1].

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The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout [1].

In comparison to fructose+P rats, rats given a high-fructose diet (i.e., 60% fructose) for 8 weeks showed significant reductions in lomerular pressure, renal vasoconstriction, and afferent arteriolar area when given febuxostat (5–6 mg/kg; i.e., daily for 4 weeks). However, rats given a normal diet showed no significant effects from febuxostat treatment alone[2]. In 5/6 Nx (5/6 nephrectomy) rats with and without concurrent hyperuricemia, febuxostat (3–4 mg/kg; po; daily for 4 weeks) combined with oxonic acid (750 mg/kg; oral gavage; daily for 4 weeks) prevents renal injury[3]. Febuxostat (2.5 mg/kg; po; daily for 12 weeks) lowers the amount of ROS in the aorta wall of atherosclerotic animals and prevents the formation of plaque in ApoE−/− mice[4]. The antidepressant effect of fruxostat (15.6 mg/kg; po; once daily for 21 days) is demonstrated by a substantial reduction in the immobility time in the forced swimming test (FST) in mice [5]. When administered in conjunction with doxorubicin (10 mg/kg; po; daily for 21 days), fruxostat (10 mg/kg; po; po; daily for 21 days) significantly reduced nephrotoxicity indicators and inflammatory mediators, restored oxidative stress biomarker levels to normal, and inhibited the expression of renal caspase-3[6].

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Increased fructose consumption is associated with hyperuricemia, metabolic syndrome, and renal damage. This study evaluated whether febuxostat (Fx), an investigational nonpurine, and selective xanthine oxidase inhibitor, could alleviate the features of metabolic syndrome as well as the renal hemodynamic alterations and afferent arteriolopathy induced by a high-fructose diet in rats. Two groups of rats were fed a high-fructose diet (60% fructose) for 8 wk, and two groups received a normal diet. For each diet, one group was treated with Fx (5-6 mg.kg(-1).day(-1) in the drinking water) during the last 4 wk (i.e., after the onset of metabolic syndrome), and the other received no treatment (placebo; P). Body weight was measured daily. Systolic blood pressure and fasting plasma uric acid (UA), insulin, and triglycerides were measured at baseline and at 4 and 8 wk. Renal hemodynamics and histomorphology were evaluated at the end of the study. A high-fructose diet was associated with hyperuricemia, hypertension, as well as increased plasma triglycerides and insulin. Compared with fructose+P, fructose+Fx rats showed significantly lowered blood pressure, UA, triglycerides, and insulin (P < 0.05 for all comparisons). Moreover, fructose+Fx rats had significantly reduced glomerular pressure, renal vasoconstriction, and afferent arteriolar area relative to fructose+P rats. Fx treatment in rats on a normal diet had no significant effects. In conclusion, normalization of plasma UA with Fx in rats with metabolic syndrome alleviated both metabolic and glomerular hemodynamic and morphological alterations. These results provide further evidence for a pathogenic role of hyperuricemia in fructose-mediated metabolic syndrome. [2]

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Results: 5/6 Nx+OA+P rats developed hyperuricemia, renal vasoconstriction and glomerular hypertension in association with further aggravation of afferent arteriolopathy compared to 5/6 Nx+V+P. Fx prevented hyperuricemia in 5/6 Nx+OA+Fx rats and ameliorated proteinuria, preserved renal function and prevented glomerular hypertension in both 5/6 Nx+V+Fx and 5/6 Nx+OA+Fx groups. Functional improvement was accompanied by preservation of afferent arteriolar morphology and reduced tubulointerstitial fibrosis. Conclusion: Fx prevented renal injury in 5/6 Nx rats with and without coexisting hyperuricemia. Because Fx helped to preserve preglomerular vessel morphology, normal glomerular pressure was maintained even in the presence of systemic hypertension.[3]

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Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE(-/-) mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(-/-) mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis. [4]

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Allopurinol and febuxostat expressed significant antidepressant like effect as indicated by reduction in the immobility period of mice in the FST as compared to control group. The effects of allopurinol and febuxostat were found to be comparable to that of fluoxetine. Conclusion: The results of the present study indicate that allopurinol and febuxostat possess significant antidepressant like activity. [5]

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Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin[6].

Enzyme assays [1]
All enzyme assays were performed using a Hitachi spectrophotometer (model U-3200) with a 6-cell positioner with the cell temperature maintained at 25°C. For all assays, the final volumes of the reaction mixtures were 2.5 mL in a 3-mL cell with a 1.0-cm light path.

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XO ASSAY [1]
The assay was conducted as described previously (Osada et al., 1993). The reaction mixture contained 0.1 M sodium phosphate buffer (pH 7.4), xanthine (2.5–20 μM) and XO (1.1 μg protein). The reaction was started by addition of enzyme, and uric acid formation (xanthine→ uric acid) was followed at 292 nm. The enzyme activity was calculated as μmol uric acid formed per min per mg protein during the initial linear portion of the reaction. The molar extinction coefficient (Δɛ292) of uric acid used in the calculation was 10,923 M−1cm−1. When inhibition of XO activity by febuxostat was studied, concentrations of xanthine were varied from 2.5 to 20 μM, and concentrations of febuxostat from 0 to 1.5 nM were tested. Inhibition mechanism was determined from Lineweaver-Burk plots, and Ki and Ki' values were calculated from Dixon plots and 1/V-axis intercept replots, respectively.

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Guanine deaminase assay [1]
The assay procedure was based on the work of Lewis and Glantz (1974). The reaction mixture contained 0.2 M sodium phosphate buffer (pH 7.0), 15 μM guanine [a substrate concentration near the Michaelis constant of 12.5 μM (Glantz and Lewis, 1978)], and guanine deaminase (0.4 μg protein). After thorough mixing, consumption of guanine (guanine→ xanthine) was monitored at 246 nm. The enzyme activity was calculated as nmol xanthine formed per min per mg protein during the initial linear portion of the reaction. The molar extinction coefficient (Δɛ246) of xanthine used in the calculation was 5,662 M−1cm−1.

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HGPRT assay [1]
The assay procedure for HGPRT activity was a modification of the method of Giacomello and Salerno (1978). The reaction mixture contained 50 mM Tris-HCl buffer (pH 8.0), 2 mM MgCl2, 0.5 mM PRPP, 1 mM DTT, 10 μM hypoxanthine [a substrate concentration near the Michaelis constant of 7.7 μM (Giacomello and Salerno, 1978)], and HGPRT (7.1 μg protein). After thorough mixing, the increase in absorbance at 245 nm resulting from formation of inosine-5′-monophosphate (IMP) (hypoxanthine → IMP) was monitored. The enzyme activity was calculated as nmol IMP formed per min per mg protein during the initial linear portion of the reaction, using the molar extinction coefficient (Δɛ245) of 1,657 M−1cm−1 for IMP.

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PNP assay [1]
This assay was carried out utilizing the method described by Stoeckler and Parks (1985). The reaction mixture contained 0.5 M potassium phosphate buffer (pH 7.5), 50 μM guanosine [a substrate concentration near the Michaelis constant of 32 μM (Stoeckler and Parks, 1985)], 1 mM DTT, and PNP (0.8 mg protein). After thorough mixing, the decrease in absorbance at 258 nm resulting from the consumption of guanosine (guanosine → guanine) was monitored. The enzyme activity was calculated as μmol guanine formed per min per mg protein during the initial linear portion of the reaction. The molar extinction coefficient (Δɛ258) for guanine used in this calculation was 5,911 M−1cm−1.

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OPRT assay [1]
The OPRT activity was assayed utilizing a modification of the method of Lieberman et al. (1955). The reaction mixture contained 50 mM Tris-HCl (pH 8.0), 2 mM MgCl2, 1 mM DTT, 15 μM OA [a substrate concentration near the Michaelis constant of 15.4 μM (Shostak et al., 1990)], 0.5 mM PRPP and OPRT (4.7 μg protein). After thorough mixing, the decrease in optical density at 295 nm, reflecting consumption of OA (OA→ OMP), was monitored. The enzyme activity was calculated as nmol of OMP formed per min per mg protein during the initial linear portion of the reaction. The molar extinction coefficient (Δɛ295) for OMP (2,997 M−1cm−1) was used in the calculation of enzyme activity.

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OMPDC assay [1]
The OMPDC activity assay was performed employing a modification of the method of Lieberman et al. (1955). The reaction mixture contained 50 mM Tris-HCl (pH 8.0), 1 mM DTT, 10 μM OMP [a substrate concentration near the Michaelis constant of 6 μM (Shostak et al., 1990)], and OMPDC (10 μg protein). After thorough mixing, the decrease in absorbance at 285 nm, reflecting consumption of OMP [OMP → uridine-5′-monophosphate (UMP)] was monitored. The enzyme activity was calculated as nmol UMP formed per min per mg protein during the initial linear portion of the reaction. The molar extinction coefficient Δɛ285 for UMP (2,285 M−1cm−1) was used in the calculation of enzyme activity.

Four groups of male Sprague-Dawley rats (n = 10/group; 290–350 g) were studied over a period of 8 wk. Two groups (normal) received a regular diet and the other two groups (fructose) were fed a 60% fructose diet to induce development of the metabolic syndrome. Details on the composition of the diets are presented in Table 1. After 4 wk, febuxostat (Fx) was administered in the drinking water (50 mg/l; ∼5–6 mg·kg−1·day−1) for an additional 4 wk in one normal-diet group (normal+Fx) and one fructose-diet group (fructose+Fx). Respective placebo (P) control groups (normal+P and fructose+P) received no treatment, except for an additional amount of NaCl in the drinking water (5.84 mg/l, to maintain a salt concentration equivalent to that of the Fx-containing water) for 4 additional wk.[2]

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5–6 mg/kg/day

Rats

Absorption
Approximately 85% of febuxostat is rapidly absorbed after oral administration. The time to peak concentration (Tmax) is 1 to 1.5 hours. After once-daily oral administration, the peak plasma concentration (Cmax) at a dose of 40 mg febuxostat is approximately 1.6 ± 0.6 mcg/mL, and at a dose of 80 mg febuxostat, it is approximately 2.6 ± 1.7 mcg/mL. A high-fat diet reduces Cmax by 49% and the area under the curve (AUC) by 18%, but does not significantly alter febuxostat's ability to lower serum uric acid levels.
Elimination Pathway
Febuxostat is primarily eliminated via the hepatic and renal pathways. After oral administration of 80 mg of radiolabeled febuxostat, approximately 49% of the dose is excreted in the urine. In urine, approximately 3% of the recovered drug dose is unchanged febuxostat, 30% is acyl glucuronide metabolites, 13% is oxidative metabolites and their conjugates, and 3% is unidentified metabolites. In feces, approximately 45% of the recovered drug dose is recovered, of which 12% is unchanged drug, approximately 1% is acyl glucuronide metabolites, 25% is oxidative metabolites and their conjugates, and 7% is unidentified metabolites.
Volume of Distribution
The apparent steady-state volume of distribution (Vss/F) of febuxostat ranges from 29 to 75 L, indicating a low to moderate volume of distribution.
Clearance
After a single oral dose of 10 to 240 mg, the mean apparent total clearance ranges from 10 to 12 L/h.

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Metabolism/Metabolites
Febuxostat is primarily metabolized in the liver by UDP-glucuronyl transferase (UGT) and cytochrome P450 (CYP) enzymes, but the relative contributions of each isoenzyme in febuxostat metabolism are not fully elucidated. UGT1A1, UGT1A3, UGT1A9, and UGT2B7 mediate the binding of febuxostat to acyl glucuronide metabolites, accounting for approximately 22% to 44% of the total administered dose. CYP1A2, CYP2C8, CYP2C9, and non-P450 enzymes are responsible for oxidation reactions, which account for 2-8% of the drug dose metabolism. Oxidation reactions produce 67M-1, 67M-2, and 67M-4, which are pharmacologically active metabolites. 67M-1, 67M-2, and 67M-4 can be further glucuronidated and sulfated. The concentration of hydroxyl metabolites in human plasma is much lower than that of the parent drug.

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Biological half-life
The apparent mean terminal elimination half-life is approximately 5 to 8 hours.

Hepatotoxicity
It has been reported that 2% to 13% (approximately 3.5% on average) of patients receiving febuxostat treatment experience abnormal liver function, but these are usually mild to moderate and self-limiting. The degree, nature, and timing of these abnormalities are not well understood. However, although no cases of jaundice or acute hepatitis have been reported, elevated liver function remains the primary cause of discontinuation of febuxostat due to adverse events in clinical trials (approximately 2%). Since febuxostat was approved and widely used, several cases of liver injury have been reported. Most cases are characterized by elevated serum transaminases without jaundice, and these occur within days of starting febuxostat treatment, including enzyme elevations in the context of DRESS syndrome. At least one case of mixed cholestatic hepatitis without immunoallergic features occurred several months after treatment. The febuxostat product information lists potential side effects such as hepatic steatosis, hepatitis, and hepatomegaly. In addition, several cases of acute liver failure occurring during febuxostat treatment have been reported in pharmacovigilance databases. Another unrelated non-purine xanthine oxidase inhibitor (benzbromarone) is not approved for use in the United States due to its potential hepatotoxicity.

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Use during pregnancy and lactation
◉Overview of use during lactation
There is currently no information regarding the use of febuxostat during lactation. Because febuxostat binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk is likely to be very low. Furthermore, its oral bioavailability is only about 50%, so the amount of drug absorbed systemically by the infant is expected to be very small. If the mother needs to use febuxostat, there is no need to discontinue breastfeeding; however, it may be preferable to choose other medications until more data are available.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding: Febuxostat binds to plasma proteins at a rate of approximately 99.2%, primarily albumin. Within the concentration range achieved at doses of 40 mg and 80 mg, plasma protein binding remained constant.

[1]. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci, 2005, 76(16), 1835-1847.

[2]. Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome. Am J Physiol Renal Physiol, 2008, 294(4), F710-F718.

[3]. Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia. Nephron Physiol, 2008, 108(4), p69-p78.

[4]. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep. 2014 Apr 1;4:4554.

[5]. Evaluation of effect of allopurinol and febuxostat in behavioral model of depression in mice. Indian J Pharmacol. 2013 May-Jun;45(3):244-7.

[6]. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats. Eur J Pharmacol. 2017 Jun 15;805:118-124.

Pharmacodynamics
Febuxostat is a novel selective xanthine oxidase/dehydrogenase inhibitor that works by dose-dependently lowering serum uric acid levels. In healthy subjects, febuxostat reduces mean serum uric acid and serum xanthine concentrations, as well as total urinary uric acid excretion. Daily administration of 40–80 mg febuxostat reduces 24-hour mean serum uric acid concentration by 40% to 55%. Febuxostat is closely associated with gout attacks, which is closely related to drug-induced reductions in serum uric acid levels and the mobilization of urate crystals from tissue deposits. Unlike allopurinol and oxypurinol, febuxostat does not inhibit the activity of other enzymes involved in the synthesis and metabolism of purines and pyrimidines because it is structurally dissimilar to purines or pyrimidines. Mechanism of Action Gout is an acute arthritis characterized by the accumulation of sodium urate and urate crystals within or around joints, leading to inflammation and persistent deposition of urate crystals in bones, joints, tissues, and other organs, and the condition may worsen over time. Hyperuricemia is closely related to gout and may have existed for many years before the first clinical gout attack; therefore, abnormal serum uric acid levels and hyperuricemia are considered biochemical abnormalities involved in the pathogenesis of gout. Xanthine oxidoreductase (XOR) can function as either xanthine oxidase or xanthine dehydrogenase. In the human body, it is a key enzyme in uric acid production because it catalyzes the oxidation of hypoxanthine to xanthine and the oxidation of xanthine to uric acid in the purine metabolic pathway. Febuxostat can potently inhibit xanthine oxidase (XOR), blocking its oxidase and dehydrogenase activities. Febuxostat binds to the molybdenum pterin active site in the XOR molecular channel with high affinity, while allopurinol has a relatively weak competitive inhibitory effect on this site. Under normal physiological conditions, XOR exists mainly in its dehydrogenase form; however, under inflammatory conditions, XOR can be converted to xanthine oxidase, catalyzing reactions that produce reactive oxygen species (ROS), such as peroxynitrite. ROS can lead to vascular inflammation and altered vascular function. Febuxostat inhibits both forms of XOR, thus suppressing ROS generation, oxidative stress, and inflammation. In rat models, febuxostat inhibits renal ischemia-reperfusion injury by reducing oxidative stress. Febuxostat is a 1,3-thiazole monocarboxylic acid, chemically named 4-methyl-1,3-thiazole-5-carboxylic acid, substituted at the 2-position with 3-cyano-4-(2-methylpropoxy)phenyl. It is an orally potent and selective xanthine oxidase inhibitor used to treat chronic hyperuricemia in patients with gout. It is an EC 1.17.3.2 (xanthine oxidase) inhibitor. It is an aromatic ether, nitrile, and 1,3-thiazole monocarboxylic acid. Febuxostat is a nonpurine xanthine oxidase (XO) inhibitor. In early 2008, febuxostat was approved by the European Commission for marketing in the treatment of chronic hyperuricemia and gout. The following year, the FDA approved febuxostat for the treatment of chronic hyperuricemia in adult patients with gout who have an inadequate response to or intolerance to allopurinol. Gout is a type of arthritis caused by the accumulation of uric acid crystals in or around joints, leading to inflammation over time and further deposition of uric acid crystals in bones, joints, tissues, and other organs. Gout is closely associated with hyperuricemia. Febuxostat's mechanism of action is to inhibit the activity of an enzyme responsible for uric acid synthesis, thereby lowering serum uric acid levels. In February 2019, the FDA added a boxed warning to febuxostat because results from a post-marketing clinical study (CARES trial) showed that patients with gout and known cardiovascular disease treated with febuxostat had an increased risk of fatal cardiovascular events compared to patients treated with allopurinol. The manufacturer and the FDA recommended that healthcare professionals use febuxostat as second-line treatment for patients who have poor response to or are intolerant to allopurinol and to avoid using febuxostat in patients with cardiovascular disease.
Febuxostat is a xanthine oxidase inhibitor. Febuxostat's mechanism of action is as a xanthine oxidase inhibitor. Febuxostat is a newly marketed non-purine xanthine oxidase inhibitor used to treat gout. Long-term use of febuxostat is associated with mild elevations in serum transaminases, but has not been found to be associated with clinically significant cases of acute liver injury. Febuxostat is an oral non-purine xanthine oxidase inhibitor that lowers uric acid levels. Oral febuxostat selectively and non-competitively inhibits the activity of xanthine oxidase. Xanthine oxidase is an enzyme that converts oxypurines (including hypoxanthine and xanthine) into uric acid. By inhibiting xanthine oxidase, uric acid production is reduced, and serum uric acid levels decrease. Febuxostat may help prevent acute renal failure caused by excessive uric acid release due to the lysis of large numbers of tumor cells during the treatment of certain malignancies. Febuxostat is a small molecule drug that has completed Phase IV clinical trials (covering all indications) and was first approved in 2009 for the treatment of gout and hyperuricemia, with 7 investigational indications. This drug has been placed on a black box warning list by the U.S. Food and Drug Administration (FDA). Febuxostat is a thiazole derivative and a xanthine oxidase inhibitor used to treat hyperuricemia in patients with chronic gout.

C16H16N2O3S

316.37

316.088

C, 60.74; H, 5.10; N, 8.85; O, 15.17; S, 10.13

144060-53-7

Febuxostat-d9;1246819-50-0;Febuxostat sodium;1140907-13-6;Febuxostat-d7;1285539-74-3

134018

White to off-white solid powder

1.3±0.1 g/cm3

536.6±60.0 °C at 760 mmHg

238-239ºC

278.3±32.9 °C

0.0±1.5 mmHg at 25°C

1.606

4.87

1

6

5

22

448

0

BQSJTQLCZDPROO-UHFFFAOYSA-N

InChI=1S/C16H16N2O3S/c1-9(2)8-21-13-5-4-11(6-12(13)7-17)15-18-10(3)14(22-15)16(19)20/h4-6,9H,8H2,1-3H3,(H,19,20)

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)