ArtNr |
S2717-5 |
Hersteller |
Selleckchem
|
CAS-Nr. |
186392-40-5 |
Menge |
5 mg |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Alias |
GP;Phosphorylase |
Similar products |
CP-91149 |
Lieferbar |
|
Administration |
Orally |
Animal Models |
Obese, diabetic male C57BL/6J-Lep(ob/ob) mice and their lean, nondiabetic C57BL/6J- /+ littermates |
Cell lines |
HSF55 and T98G |
Chemical Name |
5-chloro-N-((2S, 3R)-4-(dimethylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-1H-indole-2-carboxamide |
Concentrations |
Dissolved in DMSO, final concentrations ca.50 uM |
Description |
CP-91149 is a selective glycogen phosphorylase (GP) inhibitor with IC50 of 0.13 uM. |
Dosages |
ca.50 mg/kg |
Formulation |
Formulated in vehicle consisting of either 0.25% (wt/vol) methyl cellulose in water or 0.1% Pluronic P105 Block Copolymer Surfactant in 0.1% saline |
IC50 |
0.13 uM [1], 0.13 uM [1], 0.13 uM [1], 0.13 uM [1], 0.13 uM [1], 0.13 uM [1] |
In vitro |
CP-91149 displays 200-fold higher inhibitory activity against human liver glycogen phosphorylase a (HLGPa) than caffeine (IC50 = 26 uM). CP-91149 (10-100 uM) inhibits glucagon-stimulated glycogenolysis in isolated rat hepatocytes in a dose-dependent manner, and in primary human hepatocytes with IC50 of ca.2.1 uM. [1] CP-91149 also potently inhibits the activities of human muscle phosphorylase a and b with IC50 of 0.2 uM and ca.0.3 uM, respectively. CP-91149 treatment at 2.5 uM induces inactivation of phosphorylase and sequential activation of glycogen synthase in hepatocytes, and increases glycogen synthesis by 7-fold at 5 mM glucose and by 2-fold at 20 mM glucose. CP-91149 can partially counteract the effects of phosphorylase overexpression. [2] CP-91149 also potently inhibits brain GP with IC50 of 0.5 uM in A549 cells. CP-91149 treatment at 10-30 uM causes significant glycogen accumulation in A549 and HSF55 cells. CP-91149 treatment increases G1-phase cells with a significant reduction of the S-phase population in HSF55 cells, correlated with increased expression of p21 and p27. [3] CP-91149 also promotes the dephosphorylation and activation of GS (glycogen synthase) in non-engineered or GP-overexpressing cultured human muscle cells, but exclusively in glucose-deprived cells. [4] |
In vivo |
Oral administration of CP-91149 to diabetic ob/ob mice at 25-50 mg/kg causes rapid (3 hours) glucose lowering by 100-120 mg/dl without producing hypoglycemia, resulting from inhibition of glycogenolysis in vivo. CP-91149 treatment does not lower glucose levels in normoglycemic, nondiabetic mice. [1] In the non-fasted Goto-Kakizaki (GK) rats, administration of CP-91149 in combination with CS-917 suppresses hepatic glycogen reduction by CS-917 and decreases plasma glucose more than single administration of CS-917. [5] |
Incubation Time |
72 hours |
Kinase Assay |
Phosphorylase enzyme assay, Human liver glycogen phosphorylase a (HLGPa, 85 ng) activity is measured in the direction of glycogen synthesis by the release of phosphate from glucose-1-phosphate at 22C in 100 uL of buffer containing 50 mM Hepes (pH 7.2), 100 mM KCl, 2.5 mM EGTA, 2.5 mM MgCl2, 0.5 mM glucose-1-phosphate, and 1 mg/mL glycogen. Phosphate is measured at 620 nm, 20 minutes after the addition of 150 uL of 1 M HCl containing 10 mg/mL ammonium molybdate and 0.38 mg/mL malachite green. Increasing concentrations of CP-91149 are added to the assay in 5 uL of 14% DMSO. |
Method |
Cells are exposed to various concentrations of CP-91149 for 72hours. Viability is determined with manual cell counts following staining with trypan blue exclusion assay. Cells are fixed with 70% ethanol. DNA is stained with propidium iodide and the intensity of fluorescence is measured using a Becton-Dickinson flow cytometer at 488nm for excitation and at 650nm for emission. The cell cycle profile is analyzed using Modifit's Sync Wizard. |
Molecular Weight (MW) |
399, 87 |
Picture ChemicalStructure Description |
CP-91149 Chemical Structure |
Solubility (25C) |
DMSO 80 mg/mL, Water <1 mg/mL, Ethanol 2 mg/mL |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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