Mizagliflozin
(Synonyms: DSP-3235 free base; KGA-3235 free base; GSK-1614235 free base) 目录号 : GC60249
Mizagliflozin (KWA 0711) is a novel, potent, selective sodium glucose co-transporter 1 (SGLT1) inhibitor with Ki of 27 nM for human SGLT1. The selectivity ratio (Ki value for human SGLT2/Ki value for human SGLT1) of mizagliflozin is 303. Mizagliflozin shows the potential use for the amelioration of chronic constipation.
Cas No.:666843-10-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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- Datasheet
Mizagliflozin (KWA 0711) is a novel, potent, selective sodium glucose co-transporter 1 (SGLT1) inhibitor with Ki of 27 nM for human SGLT1. The selectivity ratio (Ki value for human SGLT2/Ki value for human SGLT1) of mizagliflozin is 303. Mizagliflozin shows the potential use for the amelioration of chronic constipation.
Mizagliflozin's inhibitory activity against SGLTs is evaluated by an in vitro assay of cells transiently expressing SGLTs. Mizagliflozin potently inhibits human SGLT1 in a highly selective manner.[1].
The oral administration of Mizagliflozin increased fecal wet weight in a dog model of loperamide-induced constipation and a rat model of low-fiber-diet-induced constipation.[1].
[1] Inoue T, et al. Eur J Pharmacol. 2017 Jul 5;806:25-31.
| Cas No. | 666843-10-3 | SDF | |
| 别名 | DSP-3235 free base; KGA-3235 free base; GSK-1614235 free base | ||
| Canonical SMILES | O=C(N)C(C)(C)CNCCCOC1=CC=C(CC2=C(C(C)C)NN=C2O[C@H]3[C@@H]([C@H]([C@@H]([C@@H](CO)O3)O)O)O)C(C)=C1 | ||
| 分子式 | C28H44N4O8 | 分子量 | 564.67 |
| 溶解度 | Methanol: 250 mg/mL (442.74 mM); DMSO: 100 mg/mL (177.09 mM) | 储存条件 | 4°C, protect from light |
| 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7709 mL | 8.8547 mL | 17.7095 mL |
| 5 mM | 0.3542 mL | 1.7709 mL | 3.5419 mL |
| 10 mM | 0.1771 mL | 0.8855 mL | 1.7709 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。
Mizagliflozin, a selective SGLT1 inhibitor, improves vascular cognitive impairment in a mouse model of small vessel disease
Pharmacol Res Perspect 2021 Oct;9(5):e00869.PMID:34586752DOI:10.1002/prp2.869.
Previously, we showed that sodium/glucose cotransporter 1 (SGLT1) participates in vascular cognitive impairment in small vessel disease. We hypothesized that SGLT1 inhibitors can improve the small vessel disease induced-vascular cognitive impairment. We examined the effects of Mizagliflozin, a selective SGLT1 inhibitor, and phlorizin, a non-selective SGLT inhibitor, on vascular cognitive impairment in a mouse model of small vessel disease. Small vessel disease was created using a mouse model of asymmetric common carotid artery surgery (ACAS). Two and/or 4 weeks after ACAS, all experiments were performed. Cerebral blood flow (CBF) was decreased in ACAS compared with sham-operated mice. Phlorizin but not Mizagliflozin reversed the decreased CBF of ACAS mice. Both Mizagliflozin and phlorizin reversed the ACAS-induced decrease in the latency to fall in a wire hang test of ACAS mice. Moreover, they reversed the ACAS-induced longer escape latencies in the Morris water maze test of ACAS mice. ACAS increased SGLT1 and proinflammatory cytokine gene expressions in mouse brains and phlorizin but not Mizagliflozin normalized all gene expressions in ACAS mice. Hematoxylin/eosin staining demonstrated that they inhibited pyknotic cell death in the ACAS mouse hippocampus. In PC12HS cells, IL-1β increased SGLT1 expression and decreased survival rates of cells. Both Mizagliflozin and phlorizin increased the survival rates of IL-1β-treated PC12HS cells. These results suggest that Mizagliflozin and phlorizin can improve vascular cognitive impairment through the inhibition of neural SGLT1 and phlorizin also does so through the improvement of CBF in a mouse model of small vessel disease.
Mizagliflozin, a novel selective SGLT1 inhibitor, exhibits potential in the amelioration of chronic constipation
Eur J Pharmacol 2017 Jul 5;806:25-31.PMID:28410751DOI:10.1016/j.ejphar.2017.04.010.
Chronic constipation is a highly common functional gastrointestinal disorder that adversely affects patient quality of life. At present, limited therapeutic options are available for the treatment of chronic constipation, which indicates the need for new therapeutic agents. Herein, we report the potential of Mizagliflozin, a novel selective sodium glucose co-transporter 1 (SGLT1) inhibitor, for the amelioration of chronic constipation. Mizagliflozin's inhibitory activity against SGLTs was evaluated by an in vitro assay of cells transiently expressing SGLTs. The safety profile of an initial single dose (2-160mg, orally) and multiple doses (2-20mg, orally, once daily immediately prior to breakfast on Days 1 and 13, and three times daily immediately prior to every meal on Days 3-12) of Mizagliflozin was determined by performing a phase I study in healthy male subjects. In addition, the effect of Mizagliflozin and lubiprostone on fecal wet weight was compared using a dog model of loperamide-induced constipation and rat model of low-fiber-diet-induced constipation. Mizagliflozin potently inhibited human SGLT1 in a highly selective manner. The results of the phase I study showed Mizagliflozin increased stool frequency and loosened stool consistency; these effects increased progressively with an increase in the dosage and the number of doses of Mizagliflozin. In addition, the oral administration of Mizagliflozin increased fecal wet weight in a dog model of loperamide-induced constipation and a rat model of low-fiber-diet-induced constipation, similar to lubiprostone. These results suggest the potential use of a novel selective SGLT1 inhibitor, Mizagliflozin, for the amelioration of chronic constipation.
Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis
Lancet Gastroenterol Hepatol 2019 Nov;4(11):831-844.PMID:31474542DOI:10.1016/S2468-1253(19)30246-8.
Background: There are several drugs available for the treatment of chronic idiopathic constipation, but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials. We did a network meta-analysis to compare the efficacy of these therapies in patients with chronic idiopathic constipation. Methods: We searched Medline, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published from inception to week 3 June, 2019, to identify randomised controlled trials assessing the efficacy of drugs (osmotic or stimulant laxatives, elobixibat, linaclotide, lubiprostone, Mizagliflozin, naronapride, plecanatide, prucalopride, tegaserod, tenapanor, or velusetrag) in adults with chronic idiopathic constipation. Participants had to be treated for a minimum of 4 weeks, and we extracted data for all endpoints preferentially at 4 weeks, 12 weeks, or both. Trials included in the analysis reported a dichotomous assessment of overall response to therapy (response or no response to therapy). We pooled the data using a random effects model, and reported efficacy and safety of all treatments as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested. To rank treatments, we used P-scores, which measure the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments. Findings: We identified 33 eligible randomised controlled trials of drugs, comprising 17 214 patients. Based on an endpoint of failure to achieve three or more complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10 mg once daily, were ranked first at 4 weeks (RR 0·55, 95% CI 0·48-0·63, P-score 0·99), and prucalopride 2 mg once daily ranked first at 12 weeks (0·82, 0·78-0·86, P-score 0·96). When response to therapy was defined as falilure to achieve an increase of one or more CSBM per week from baseline, diphenyl methane laxatives at a dose of 10 mg once daily ranked first at 4 weeks (0·44, 0·37-0·54, P-score 0·99), with prucalopride 4 mg once daily ranked first at 12 weeks (0·74, 0·66-0·83, P-score 0·79), although linaclotide 290 μg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively). Bisacodyl ranked last in terms of safety for total number of adverse events and abdominal pain (P-score 0·08). Interpretation: Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown. Funding: None.
Absorption, disposition, metabolism and excretion of [14C]Mizagliflozin, a novel selective SGLT1 inhibitor, in rats
Xenobiotica 2019 Apr;49(4):463-473.PMID:29558223DOI:10.1080/00498254.2018.1449269.
The pharmacokinetic and metabolite profiles of Mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [14 C]Mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [14 C]Mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [14 C]Mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered Mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, Mizagliflozin is rapidly cleared from circulation.
Safety and efficacy of the sodium-glucose cotransporter 1 inhibitor Mizagliflozin for functional constipation: a randomised, placebo-controlled, double-blind phase 2 trial
Lancet Gastroenterol Hepatol 2018 Sep;3(9):603-613.PMID:30056028DOI:10.1016/S2468-1253(18)30165-1.
Background: Mizagliflozin is a novel oral sodium-glucose cotransporter 1 (SGLT1) inhibitor that increases luminal glucose and water. This study assessed the efficacy and safety of Mizagliflozin in patients with functional constipation. Methods: In this multicentre, randomised, double-blind phase 2 trial at 32 hospitals and community outpatient clinics in Japan, we enrolled patients with functional constipation or constipation-predominant irritable bowel syndrome, aged 20 years or older. Patients were randomly assigned (1:1:1), by use of an independent centralised registration system and dynamic allocation method, to receive Mizagliflozin 5 mg, Mizagliflozin 10 mg, or placebo, orally once daily for 4 weeks. Patients, investigators, staff, and the sponsor were blinded to the group assignments. The primary outcome was the change from baseline in the number of spontaneous bowel movements per week after 1 week. Efficacy analysis was done in all patients except those who deviated from good clinical practice, did not receive at least one dose of the study drug, withdrew before starting treatment, were ineligible, or for whom the primary outcome could not be assessed, and safety was assessed in all patients except those who deviated from good clinical practice, who did not receive the study drug, or who withdrew before receiving treatment. This trial is registered with ClinicalTrials.gov, number NCT02281630, and is completed. Findings: Between Oct 15, 2014, and March 7, 2015, 258 patients with functional constipation were randomly assigned: 86 patients per group. Two patients from the placebo group and three from the 10 mg Mizagliflozin group were excluded because the primary outcome could not be assessed, and one patient from the 5 mg Mizagliflozin group was excluded for not receiving the study drug; therefore 84 patients in the placebo group, 85 in the 5 mg Mizagliflozin group, and 83 in the 10 mg Mizagliflozin group were included in the full analysis population. Mean change from baseline in the number of spontaneous bowel movements per week after 1 week with Mizagliflozin 5 mg (3·85 [SD 3·96]) and Mizagliflozin 10 mg (5·85 [6·01]) was significantly greater than those in the placebo group (1·80 [1·80]; p<0·0001 for both comparisons). The most common adverse events were nasopharyngitis (one [1%] of 86 patients in the placebo group, seven [8%] of 85 on Mizagliflozin 5 mg, and five [6%] of 86 on Mizagliflozin 10 mg), diarrhoea (none on placebo, four [5%] patients on Mizagliflozin 5 mg, and eight [9%] on Mizagliflozin 10 mg), and abdominal distention (three [3%] on placebo, four [5%] on Mizagliflozin 5 mg, and seven [8%] on Mizagliflozin 10 mg). Only diarrhoea and abdominal distention were deemed to be related to Mizagliflozin treatment, whereas nasophanyngitis might not be related to Mizagliflozin treatment, on the basis of clinical evaluation. Interpretation: The SGLT1 inhibitor Mizagliflozin showed favourable efficacy and tolerability at 5 mg and 10 mg doses in patients with functional constipation, providing a potential alternative therapy to available drugs. Funding: Kissei Pharmaceutical.