K-757
K-757 is an orally active, gut-targeted GPR40 agonist with EC50 values of 2.1 nM, 5.6 nM, 4.2 nM and 166 nM in humans, mice, rats and dogs, respectively. K-757 activates nutrient receptors co-expressed on pancreatic β cells and intestinal enteroendocrine cells. K-757 mediates and induces the secretion of satiety hormones GLP-1 and PYY in multiple in vitro and in vivo models. When used in combination with GPR119 agonist K-833, K-757 acts as a potentiator to elevate circulating levels of satiety hormones. K-757 can be used in the research of type 2 diabetes, weight loss and other related metabolic disorders.
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- No. CAS: 2696409-13-7
- Fòrmula: C32H48NO4P
- Peso molecular:541.70
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Almacenamiento:
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Actividad biológica
Descripciòn
IC50 & Target
[2]|
hGPR40 2.1 nM (EC50) |
Mice GPR40 5.6 nM (EC50) |
Rat GPR40 4.2 nM (EC50) |
Dog GPR40 166 nM (EC50) |
GLP-1 |
In Vitro
K-757 (1-30 μM; 2.5 h) induces concentration-dependent GLP-1 secretion in wild-type mouse colonic crypt cultures via GPR40 activation, with no activity observed in GPR40 knockout cultures[2].
K-757 (0.01-30 μM; 2.5 h) induces concentration-dependent GLP-1 and PYY secretion in human ileal crypt cultures, with maximal responses at 10 and 30 μM[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
Parmacokinetics
| Species | Dose | Route | CLplasma | Vdss | T1/2 | Cmax | Bioavailability |
|---|---|---|---|---|---|---|---|
| Mice[2] | 3 mg/kg | p.o. | 11 mL/min/kg | 0.55 L/kg | 1.0 h | 43 nM | 1.7 % |
| Mice[2] | 1 mg/kg | i.v. | 11 | 0.55 L/kg | 1.0 h | / | / |
| Rat[2] | 10 mg/kg | p.o. | 4.1 mL/min/kg | 0.26 L/kg | 2.6 h | 116 nM | 0.8 % |
| Rat[2] | 1 mg/kg | i.v. | 4.1 mL/min/kg | 0.26 L/kg | 2.6 h | / | / |
| Dog[2] | 2 mg/kg | p.o. | 7.2 mL/min/kg | 0.53 L/kg | 11 h | 225 nM | 13 % |
| Dog[2] | 1 mg/kg | i.v. | 7.2 mL/min/kg | 0.53 L/kg | 11 h | / | / |
| Monkey[2] | 2 mg/kg | p.o. | 4.1 mL/min/kg | 0.41 L/kg | 8.1 h | 49 nM | 1.1 % |
| Monkey[2] | 1 mg/kg | i.v. | 4.1 mL/min/kg | 0.41 L/kg | 8.1 h | / | / |
In Vivo
K-757 (0.3-30 mg/kg; p.o.; single dose, co-administered with K-833 30 mg/kg) in combination with K-833 induces enhanced GLP-1 secretion in fasted C57BL/6J mice, with maximal efficacy achieved at a 3 mg/kg single dose of K-757[2].
K-757 (10 mg/kg; p.o.; single dose) induces sustained GLP-1 secretion in fasted male Beagle dogs for at least 5 hours postdose[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J (male, 10−12 weeks old)[2]
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Dosage:3 mg/kg; 10 mg/kg; 30 mg/kg; 60 mg/kg
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Administration:p.o.; single dose
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Result:Elicited dose-dependent increases in plasma GLP-1 levels 1 hour postdose.
Achieved maximal efficacy at 10 mg/kg, resulting in GLP-1 levels of ~100 pg/mL.
Induced no GLP-1 secretion at 60 mg/kg in GPR40 knockout mice.
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Animal Model:C57BL/6J (male, 10−12 weeks old)[2]
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Dosage:0.3 mg/kg; 1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg (co-administered with K-833 30 mg/kg)
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Administration:p.o.; single dose
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Result:Resulted in enhanced GLP-1 secretion that plateaued at 3 mg/kg, reaching GLP-1 levels of ~90 pg/mL.
Achieved active GLP-1 levels of ~6 pg/mL when 30 mg/kg was combined with K-833 30 mg/kg.
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Animal Model:Beagle (male, >6 months old, 6−12 kg body weight)[2]
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Dosage:10 mg/kg
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Administration:p.o.; single dose
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Result:Resulted in significant elevation of plasma GLP-1 levels evident as early as 1 hour postdose.
Reached peak GLP-1 levels of ~90 pg/mL at 1.5 hours postdose.
Maintained elevated GLP-1 levels for at least 5 hours.
Ensayo clínico
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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No. CAS 2696409-13-7
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Peso molecular 541.70
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Fòrmula C32H48NO4P
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SMILES
COC1=CC=C(CCCC(C)(C)C)C(N2CCC(COC3=CC=CC([C@H](C4CC4)CP(O)(C)=O)=C3)CC2)=C1
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocolo
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Research Protocol for Metabolic Diseases
AMP-activated protein kinase, AMPK, is a conserved cellular energy sensor that responds to reduced cellular energy status and coordinates metabolism by increasing ATP-generating catabolic pathways while suppressing ATP-consuming anabolic processes. In metabolic disease research, the AMPK pathway is experimentally relevant because it regulates hepatic lipid synthesis, fatty acid oxidation, glucose production, skeletal-muscle glucose disposal, mTORC1-linked biosynthesis, autophagy, mitochondrial homeostasis, and whole-body energy balance. The central pathway logic is that energy stress, metformin, exercise-like stimulation, or direct AMPK activators increase AMPKα Thr172 phosphorylation and downstream substrate phosphorylation, including ACC and RAPTOR. Phosphorylation of ACC suppresses lipogenesis and supports fatty acid oxidation, whereas phosphorylation of RAPTOR suppresses mTORC1 signaling and links cellular energy status to growth and protein synthesis control. The pathway is linked
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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