Dotinurad
(Synonyms: 3-(3,5-二氯-4-羟基苯甲酰基)-1,1-二氧代-2,3-二氢-1,3-苯并噻唑) 目录号 : GC35895
Dotinurad (FYU-981), a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 (URAT1) with IC50 of 37.2 nM.
Cas No.:1285572-51-1
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Dotinurad (FYU-981), a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 (URAT1) with IC50 of 37.2 nM.
[1] Ishikawa T, et al. Expert Opin Pharmacother. 2021 Aug;22(11):1397-1406.
| Cas No. | 1285572-51-1 | SDF | |
| 别名 | 3-(3,5-二氯-4-羟基苯甲酰基)-1,1-二氧代-2,3-二氢-1,3-苯并噻唑 | ||
| Canonical SMILES | O=C(C1=CC(Cl)=C(O)C(Cl)=C1)N(C2)C3=CC=CC=C3S2(=O)=O | ||
| 分子式 | C14H9Cl2NO4S | 分子量 | 358.2 |
| 溶解度 | DMSO: 65 mg/mL (181.46 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.7917 mL | 13.9587 mL | 27.9174 mL |
| 5 mM | 0.5583 mL | 2.7917 mL | 5.5835 mL |
| 10 mM | 0.2792 mL | 1.3959 mL | 2.7917 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Dotinurad: a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia and gout
Expert Opin Pharmacother 2021 Aug;22(11):1397-1406.PMID:33926357DOI:10.1080/14656566.2021.1918102.
Introduction: Gout is an inflammatory disease triggered by deposition of urate crystals secondary to longstanding hyperuricemia, and its management implies both the treatment of flares and management of hyperuricemia. Dotinurad is a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 in the apical surface of renal proximal tubular cells, and has been approved for the treatment of gout and hyperuricemia in Japan. Areas covered: This overview of Dotinurad covers nonclinical and clinical pharmacology studies in special populations and its efficacy and safety in Japanese hyperuricemic patients with and without gout. Expert opinion: Dotinurad, as an SURI, is expected to inhibit urate reabsorption more effectively than conventional urate-lowering agents. It is noninferior to benzbromarone or febuxostat in reducing serum urate levels in hyperuricemic patients with or without gout. Its efficacy is not attenuated in patients with mild to moderate renal impairment or with hepatic impairment. At a maintenance dose of 2 or 4 mg once daily, most patients achieved the target serum urate level of ≤6 mg/dL in a long-term study. No findings that raised safety concerns, including liver injury, were identified. Dotinurad is expected to be a new therapeutic option in hyperuricemic patients with and without gout.
Dotinurad: a novel selective urate reabsorption inhibitor as a future therapeutic option for hyperuricemia
Clin Exp Nephrol 2020 Mar;24(Suppl 1):1-5.PMID:31754883DOI:10.1007/s10157-019-01811-9.
Gout is a chronic inflammatory disease caused by precipitation of urate crystals in the joints, kidneys, and urinary tract. Independent of urate deposition disorders, recent studies have shown a positive association between circulating uric acid (UA) levels and cardiovascular (CV) diseases. These results indicate that UA is a precipitating factor of both gout and the progression of CV diseases, including hypertension and/or chronic kidney disease (CKD). A large body of evidence has shown that UA-lowering therapies are effective in preventing the progression of hypertension/CKD and that a causal relationship exists between serum UA level and CV diseases. Despite the urgent need for effective UA-lowering drugs that can be used to obtain better therapeutic outcomes and prognosis, only few drugs have been developed in the past decades. Recently, febuxostat and topiroxostat, which are xanthine oxidoreductase inhibitors, were developed and used in clinical practice. Of note, after the approval of lesinurad, which is a urate transporter-1 (URAT-1) inhibitor, in the United States in 2015, Dotinurad (Fig. 1), a novel promising drug with selective UA reabsorption inhibitory property, was recently developed in Japan in 2018. Dotinurad is indicated for patients with hyperuricemia/gout as most patients with hyperuricemia are classified into "underexcretion type", which requires the inhibition of URAT-1 to excrete excess UA via the kidney. Focusing on Dotinurad, the present study highlighted the multifaceted preliminary new trials that assessed for drug efficacy and safety, pharmacokinetics (PK) according to age and gender, the presence or absence of liver and kidney disorders, drug interactions with NSAID, and non-inferiority of Dotinurad to either febuxostat or benzbromarone. A series of studies included in this supplemental review indicate that Dotinurad reduces serum UA levels, and its efficacy and safety are similar to those of other UA-lowering agents currently used even in hyperuricemic patients with various clinical conditions. Moreover, two exploratory studies with a small sample size were conducted to compare PK parameters between patients with overproduction- and underexcretion-type hyperuricemia, and results showed that the effects of UA-lowering agents were comparable between the two subtype groups.Fig. 1Chemical structural formula of Dotinurad.
Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor
J Pharmacol Exp Ther 2019 Oct;371(1):162-170.PMID:31371478DOI:10.1124/jpet.119.259341.
The effect of Dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ 6-1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents-namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC50 values of 0.0372, 0.190, 30.0, and 165 μM, respectively. Dotinurad weakly inhibited ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and OAT3, with IC50 values of 4.16, 4.08, and 1.32 μM, respectively, indicating higher selectivity for URAT1. The hypouricemic effects of Dotinurad and benzbromarone were evaluated in Cebus monkeys. Dotinurad, at doses of 1-30 mg/kg, concomitantly decreased plasma urate levels and increased fractional excretion of urate (FEUA) in a dose-dependent manner. On the contrary, benzbromarone, at a dose of 30 mg/kg, showed a modest effect on plasma urate levels. The inhibitory effect of Dotinurad on urate secretion transporters was evaluated in Sprague-Dawley rats, with sulfasalazine and adefovir as probe substrates of ABCG2 and OAT1, respectively. Drugs, including febuxostat as a reference ABCG2 inhibitor, were administered orally before sulfasalazine or adefovir administration. Dotinurad had no effect on urate secretion transporters in vivo, whereas benzbromarone, lesinurad, probenecid, and febuxostat increased the plasma concentrations of probe substrates. These results suggested Dotinurad is characterized as a selective urate reabsorption inhibitor (SURI), which is defined as a potent URAT1 inhibitor with minimal effect on urate secretion transporters, including ABCG2 and OAT1/3, because of its high efficacy in decreasing plasma urate levels compared with that of other uricosuric agents. SIGNIFICANCE STATEMENT: Our study on the inhibitory effects on urate transport showed that Dotinurad had higher selectivity for urate transporter 1 (URAT1) versus ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter (OAT) 1/3 compared to other uricosuric agents. In Cebus monkeys, Dotinurad decreased plasma urate levels and increased fractional excretion of urate in a dose-dependent manner. To determine the inhibitory effect of Dotinurad on urate secretion transporters, we studied the movement of substrates of ABCG2 and OAT1 in rats. Dotinurad had no effect on these transporters, whereas the other uricosuric agents increased the plasma concentrations of the substrates. These results suggested Dotinurad as a potent and selective urate reabsorption inhibitor is characterized by increased efficacy with decreasing plasma urate levels.
URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice
Mol Metab 2022 Jan;55:101411.PMID:34863940DOI:10.1016/j.molmet.2021.101411.
Objective: Accumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice. Methods: Mice fed a high-fat diet (HFD) for 16-18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (Dotinurad [50 mg/kg/day]) for another 4 weeks. Results: We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by Dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by Dotinurad via UCP1 activation. Conclusions: In conclusion, a novel URAT1-selective inhibitor, Dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.
Ideal pharmacokinetic profile of Dotinurad as a selective urate reabsorption inhibitor
Drug Metab Pharmacokinet 2020 Jun;35(3):313-320.PMID:32327267DOI:10.1016/j.dmpk.2020.03.002.
Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of Dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0.257, 0.205, and 0.182 L/kg, respectively) and oral clearance (0.054, 0.037, and 0.013 L·h-1·kg-1, respectively) of Dotinurad were very low, whereas plasma and luminal concentrations were adequately maintained at high levels. In addition, species differences were scarcely observed with plasma protein binding of 99.4%. The main metabolite was Dotinurad glucuronide (no specific metabolites in humans), and percentage excretion of unchanged Dotinurad was low in all the investigated species. The risk of drug interaction with Dotinurad was expected to be low, because it weakly inhibits metabolic enzymes such as cytochrome P450 (CYP). In conclusion, low-dose Dotinurad exhibited excellent pharmacological effects as well as ideal PK properties as a SURI.