MK-0941
目录号 : GC44210
A glucokinase activator
Cas No.:1137916-97-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
MK-0941 is a glucokinase activator with EC50 values of 0.24 and 0.065 µM at low (2.5 mM) and high (10 mM) concentrations of glucose, respectively. It increases insulin secretion from isolated rat islets of Langerhans and glucose uptake by hepatocytes in vitro. MK-0941 reduces blood glucose levels in high-fat diet-fed db/db mice and in high-fat diet-fed mice with diabetes induced by streptozotocin .
| Cas No. | 1137916-97-2 | SDF | |
| Canonical SMILES | CCS(C1=CC=C(OC2=CC(O[C@@H](C)CO)=CC(C(NC3=NN(C)C=C3)=O)=C2)C=N1)(=O)=O.O=S(O)(C)=O | ||
| 分子式 | C21H24N4O6S•CH3SO3H | 分子量 | 556.6 |
| 溶解度 | DMF: 20 mg/ml,DMSO: 20 mg/ml,Ethanol: 5 mg/ml | 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。 |
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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 | 1.7966 mL | 8.9831 mL | 17.9662 mL |
| 5 mM | 0.3593 mL | 1.7966 mL | 3.5932 mL |
| 10 mM | 0.1797 mL | 0.8983 mL | 1.7966 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。
Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes
Diabetes Care 2011 Dec;34(12):2560-6.PMID:21994424DOI:10.2337/dc11-1200.
Objective: To assess the efficacy and safety of MK-0941, a glucokinase activator (GKA), when added to stable-dose insulin glargine in patients with type 2 diabetes. Research design and methods: In this double-blind study, 587 patients taking stable-dose insulin glargine (±metformin ≥1,500 mg/day) were randomized (1:1:1:1:1) to MK-0941 10, 20, 30, or 40 mg or matching placebo t.i.d. before meals (a.c.). This study included an initial 14-week, dose-ranging phase followed by a 40-week treatment phase during which patients were to be uptitrated as tolerated to 40 mg (or placebo) t.i.d. a.c. The primary efficacy end point was change from baseline in A1C at Week 14. Results: At Week 14, A1C and 2-h postmeal glucose (PMG) improved significantly versus placebo with all MK-0941 doses. Maximal placebo-adjusted least squares mean changes from baseline in A1C (baseline A1C 9.0%) and 2-h PMG were -0.8% and -37 mg/dL (-2 mmol/L), respectively. No significant effects on fasting plasma glucose were observed at any dose versus placebo. By 30 weeks, the initial glycemic responses noted at 14 weeks were not sustained. MK-0941 at one or more doses was associated with significant increases in the incidence of hypoglycemia, triglycerides, systolic blood pressure, and proportion of patients meeting criteria for predefined limits of change for increased diastolic blood pressure. Conclusions: In patients receiving stable-dose insulin glargine, the GKA MK-0941 led to improvements in glycemic control that were not sustained. MK-0941 was associated with an increased incidence of hypoglycemia and elevations in triglycerides and blood pressure.
Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs
Mol Pharmacol 2011 Dec;80(6):1156-65.PMID:21937665DOI:10.1124/mol.111.074401.
Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic β cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA 3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (MK-0941). Incubated in vitro with recombinant human glucokinase, 1 μM MK-0941 lowered the S(0.5) of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC(50) values for activation of GK by MK-0941 were 0.240 and 0.065 μM, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 μM MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and nondiabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ~2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve postchallenge (0-2 h) plasma glucose levels by up to 48% compared with vehicle-treated controls. When administered twice daily to mice for 16 days, and once daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.
Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
PLoS One 2022 Mar 21;17(3):e0265761.PMID:35312718DOI:10.1371/journal.pone.0265761.
Glucokinase activators are regarded as potent candidates for diabetes treatment, however, in clinical studies on patients with type 2 diabetes, a diminishing efficacy was observed after chronic treatment with them. The mechanism of this reduction has not been elucidated, and whether it is a class effect of glucokinase activators remains inconclusive. Here, we firstly identified a diabetic animal model that shows the diminished efficacy after long-term treatment with MK-0941, a glucokinase activator that exhibited diminished efficacy in a clinical study, and we analyzed the mechanism underlying its diminished efficacy. In addition, we evaluated the long-term efficacy of another glucokinase activator, TMG-123. Goto-Kakizaki rats were treated with MK-0941 and TMG-123 for 24 weeks. The results showed that glycated hemoglobin A1C levels and plasma glucose levels decreased transiently but increased over time with the continuation of treatment in the MK-0941-treated group, while decreased continuously in the TMG-123-treated group. Only in the TMG-123-treated group, higher plasma insulin levels were shown at the later stage of the treatment period. For the mechanism analysis, we conducted a hepatic enzyme assay and liver perfusion study in Goto-Kakizaki rats after chronic treatment with MK-0941 and TMG-123, and revealed that, only in the MK-0941-treated group, the activity of glucose-6-phosphatase was increased, and hepatic glucose utilization was decreased compared to the non-treated group. These data indicate that disruptions in hepatic glucose metabolism are involved in the diminished efficacy of glucokinase activators.
Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate
AAPS J 2015 Nov;17(6):1492-500.PMID:26290380DOI:10.1208/s12248-015-9816-7.
In vitro-in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus(TM) Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.