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Purity: ≥98%
| Targets |
GPR119
GSK1292263 targets the GPR119 receptor. GPR119 is a class A (rhodopsin-type) orphan GPCR. GSK1292263 acts as a potent and selective agonist at this receptor. It has a pEC50 of 6.9 for the human GPR119 receptor and a pEC50 of 6.7 for the rat receptor. By activating GPR119, it enhances glucose-dependent insulin secretion and upregulates incretin hormones like GLP-1. |
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| ln Vitro |
GSK1292263 is a novel, potent GPR119 agonist, which showed potential for the treatment of type 2 diabetes. It is currently undergoing phase 2 clinical trial for type 2 diabetes. GSK1292263 improves glucose regulation in animal models of diabetes, but has no effect on plasma glucose in type 2 diabetics. GSK1292263 treatment displayed little inhibition towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), p-GP, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition 1.
Kinase Assay: GSK-1292263 is selected from 1538 compounds by using Hypo1, the Fit-Value and Estimate of GSK-1292263 that is aligned in Hypo1 are 8.8 and 7.7 (nM), respectively Cell Assay: In vitro, GSK1292263 treatment displayed little inhibition towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), p-GP, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition 1. In vitro, GSK1292263 has been characterized as a potent GPR119 agonist. It was selected from a set of 1538 compounds based on its activity. Its predicted EC50 against GPR119 in vitro is in the nanomolar range, with fitting and estimated values of 8.8 and 7.7 nM, respectively, in one study. It exhibits potent and selective activity. |
| ln Vivo |
In type 2 diabetic rats, GSK1292263 increases glucose-dependent insulin production, upregulates glucagon-like peptide-1, and promotes glucose homeostasis[2].
In neonatal STZ rats: a single oral dose of GSK1292263 (30 mg/kg) administered 30 minutes before an OGTT (glucose load 2 g/kg) resulted in a numerically lower AUC of plasma glucose compared with vehicle, but the effect was not statistically significant. After 14 days of once-daily oral dosing (30 mg/kg/day), the OGTT performed on day 14 showed no statistically significant glucose-lowering effect compared with vehicle. All three tested compounds (DS-8500a, GSK1292263, MBX-2982) had no effect on plasma fasting glucose levels after 2 weeks of treatment. [2] In human clinical trials: a single dose of GSK1292263 (25-800 mg) showed a tendency to reduce glucose incremental AUC during OGTT, but there was no reduction in weighted-mean glucose AUC after 13 or 14 days of dosing in a phase 2 trial. [2] In vivo, GSK1292263 is an orally active compound. It upregulates glucagon-like peptide-1 and enhances glucose-dependent insulin secretion, improving glucose homeostasis in type 2 diabetic rats. It elevates circulating glucose-dependent insulinotropic peptide, GLP-1, and peptide tyrosine-tyrosine in nonclinical models of diabetes. It has been investigated in clinical trials for type 2 diabetes, reaching Phase 2. |
| Enzyme Assay |
Non-cellular binding assays for GSK1292263 involve measuring its affinity for the GPR119 receptor. These assays typically use membrane preparations from cells expressing the receptor to study the displacement of a labeled ligand. Its pEC50 values for the human and rat receptors are key parameters determined in these experiments. Such assays are essential for characterizing its potency as a GPR119 agonist.
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| Cell Assay |
In vitro cell-based assays for GSK1292263 are used to study its functional effects. These assays often involve cells expressing the GPR119 receptor, where the compound's ability to activate downstream signaling pathways, such as cAMP accumulation, is measured. These studies help to confirm its mechanism of action as a GPR119 agonist.
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| Animal Protocol |
Animal/Disease Models: Male neonatal Streptozotocin (STZ)-induced SD rats (7 weeks of age)[2]
Doses: 30 mg/kg Route of Administration: Orally given; one time/day for 2 weeks Experimental Results: The AUC of plasma glucose (AUCPG) in the single treatment of the GSK1292263 group was numerically lower than that of the vehicle group, but the effect was modest . Male neonatal streptozotocin-induced SD rats (7 weeks of age) were used. GSK1292263 was administered orally at a dose of 30 mg/kg once daily for 2 weeks. On day 0 and day 14, an oral glucose tolerance test (OGTT) was performed. Rats were fasted overnight and then given the compound orally. Thirty minutes later, all animals received a 50% glucose solution orally at a dose of 2 g/kg. Blood was collected from the tail vein at -30 minutes (prior to compound administration), -5 minutes (before glucose load), and at 30, 60, 120, and 180 minutes after the glucose load. Plasma glucose levels were measured, and the AUC of plasma glucose from -5 to 180 minutes after glucose load was calculated. [2] In vivo animal studies for GSK1292263 have been conducted in type 2 diabetic rat models. The compound is typically administered orally. Endpoints in these studies include measurements of glucose homeostasis, insulin secretion, and incretin hormone levels. These studies are crucial for validating its in vivo efficacy as an antidiabetic agent. |
| ADME/Pharmacokinetics |
GSK1292263 is an orally active compound. It has a molecular weight of 497.47 g/mol. As a small molecule agonist, it is expected to be well-absorbed after oral administration. Its pharmacokinetic profile has been studied in preclinical models and clinical trials. It is a research compound that has been investigated in clinical trials.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for GSK1292263 are not extensively detailed in standard summaries, as it is a research compound that did not progress to approval. As with all investigational drugs, its safety profile would have been evaluated in preclinical and clinical studies. GSK1292263 is not an approved drug and is available only as a research compound.
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| References | |
| Additional Infomation |
GSK1292263 has been studied for the treatment of type 2 diabetes.
GSK1292263 contains a piperidine ring in its chemical structure, which may be associated with an antagonist conformer and lower intrinsic activity. It has been associated with loss of efficacy in short-term repeat-dosing studies in clinical development. In the repeat-dosing study described in this paper, no obvious loss of efficacy was observed, but the glucose-lowering efficacy level was modest and not statistically significant. [2] GSK1292263 is a novel, potent, and orally active GPR119 receptor agonist. It was investigated for the treatment of type 2 diabetes mellitus and reached Phase 2 clinical trials. By activating GPR119, it enhances glucose-dependent insulin secretion and upregulates incretin hormones like GLP-1. GSK1292263 is not an approved drug and is available only as a research compound. |
| Molecular Formula |
C23H28N4O4S
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| Molecular Weight |
456.56
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| Exact Mass |
456.183
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| CAS # |
1032823-75-8
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| Related CAS # |
1032823-75-8;1032824-54-6 (HCl);
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| PubChem CID |
24996872
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
655.1±65.0 °C at 760 mmHg
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| Flash Point |
350.0±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.565
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| LogP |
1.67
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
32
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| Complexity |
685
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C1=NOC(N2CCC(CC2)COC3=CN=C(C=C3)C4=CC=C(C=C4)S(C)(=O)=O)=N1)C
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| InChi Key |
AYJRTVVIBJSSKN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H28N4O4S/c1-16(2)22-25-23(31-26-22)27-12-10-17(11-13-27)15-30-19-6-9-21(24-14-19)18-4-7-20(8-5-18)32(3,28)29/h4-9,14,16-17H,10-13,15H2,1-3H3
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| Chemical Name |
5-[4-[[6-(4-methylsulfonylphenyl)pyridin-3-yl]oxymethyl]piperidin-1-yl]-3-propan-2-yl-1,2,4-oxadiazole
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 34 mg/mL (74.5 mM)
Water: 1 mg/mL (Insoluble) Ethanol: 1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (4.38 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 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1903 mL | 10.9515 mL | 21.9029 mL | |
| 5 mM | 0.4381 mL | 2.1903 mL | 4.3806 mL | |
| 10 mM | 0.2190 mL | 1.0951 mL | 2.1903 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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