(2R,3S)-3-[(5-chloro-1H-indol-2-yl)formamido]-2-hydroxy-N,N-dimethyl-4-phenylbutanamide

• ChemBase ID: 73187
• Molecular Formular: C21H22ClN3O3
• Molecular Mass: 399.87068
• Monoisotopic Mass: 399.13496926
• SMILES: c1(ccc2c(c1)cc([nH]2)C(=O)N[C@H]([C@H](C(=O)N(C)C)O)Cc1ccccc1)Cl
• Canonical SMILES: Clc1ccc2c(c1)cc([nH]2)C(=O)N[C@H]([C@H](C(=O)N(C)C)O)Cc1ccccc1
• InChI: InChI=1S/C21H22ClN3O3/c1-25(2)21(28)19(26)17(10-13-6-4-3-5-7-13)24-20(27)18-12-14-11-15(22)8-9-16(14)23-18/h3-9,11-12,17,19,23,26H,10H2,1-2H3,(H,24,27)/t17-,19+/m0/s1
• InChIKey: HINJNZFCMLSBCI-PKOBYXMFSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2R,3S)-3-[(5-chloro-1H-indol-2-yl)formamido]-2-hydroxy-N,N-dimethyl-4-phenylbutanamide
• IUPAC Traditional name: (2R,3S)-3-[(5-chloro-1H-indol-2-yl)formamido]-2-hydroxy-N,N-dimethyl-4-phenylbutanamide
• Synonyms: CP-91149; 2-Methyl-2-[3-[(3S)-1-[[4-(1-methylethyl)phenyl]acetyl]-3-piperidinyl]phenoxy]propanoic Acid; CP 775146; (S)-2-[3-[1-[(4-Isopropylphenyl)acetyl]piperidin-3-yl]phenoxy]-2-methylpropionic Acid; PF-06340672; CP-775146; 5-Chloro-N-[(1S,2R)-3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide; CP-91149

Database IDs

• CAS Number: 186392-40-5; 702680-17-9
• MDL Number: MFCD00954145
• PubChem SID: 162038107
• PubChem CID: 9843900

CALCULATED PROPERTIES

• Acid pKa: 12.074857
• H Acceptors: 3
• H Donor: 3
• LogD (pH = 5.5): 2.3835182
• LogD (pH = 7.4): 2.38351
• Log P: 2.3835185
• Molar Refractivity: 108.5775 cm^3
• Polarizability: 42.705753 Å^3
• Polar Surface Area: 85.43 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO; DMSO: >20 mg/mL; Methanol
• Apperance: Off-White Solid; white to off-white powder
• Melting Point: 70-76°C

Safety Information

• Storage Condition: -20°C; Refrigerator
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 22
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H302
• Storage Temperature: 2-8°C

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C21H22ClN3O3

DETAILS

Selleck Chemicals - S2717

Research Area

• Description: Cancer

Biological Activity

• Description: CP-91149 is a selective glycogen phosphorylase (GP) inhibitor with IC50 of 0.13 μM.
• Targets: GP
• IC50: 0.13 μM ^[1]
• In Vitro: CP-91149 displays 200-fold higher inhibitory activity against human liver glycogen phosphorylase a (HLGPa) than caffeine (IC50 = 26 μM). CP-91149 (10-100 μM) inhibits glucagon-stimulated glycogenolysis in isolated rat hepatocytes in a dose-dependent manner, and in primary human hepatocytes with IC50 of ~2.1 μM. ^[1] CP-91149 also potently inhibits the activities of human muscle phosphorylase a and b with IC50 of 0.2 μM and ~0.3 μM, respectively. CP-91149 treatment at 2.5 μM 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 μM in A549 cells. CP-91149 treatment at 10-30 μM 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]

Combination Therapy

• Description: HLGPa inhibition by CP-91149 is synergistic with caffeine and theophylline, as caffeine or theophylline increases the potency (IC50) of CP-91149 from 1 μM to 0.14 μM. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• 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 22°C in 100 μL 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 μL 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 μL of 14% DMSO.
• Protocol: Cell Assay ^[3]
• Cell Lines: HSF55 and T98G
• Concentrations: Dissolved in DMSO, final concentrations ~50 μM
• Incubation Time: 72 hours
• Methods: 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.
• Protocol: Animal Study ^[1]
• Animal Models: Obese, diabetic male C57BL/6J-Lep^(ob/ob) mice and their lean, nondiabetic C57BL/6J-?/+ littermates
• 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
• Doses: ~50 mg/kg
• Administration: Orally

References

• References: [1] Martin WH, et al. Proc Natl Acad Sci U S A, 1998, 95(4), 1776-1781.
• References: [2] Aiston S, et al. J Biol Chem, 2001, 276(26), 23858-23866.
• References: [3] Schnier JB, et al. Biochem Biophys Res Commun, 2003, 309(1), 126-134.
• References: [4] Lerín C, et al. Biochem J, 2004, 378(Pt 3), 1073-1077.
• References: [5] Yoshida T, et al. J Pharmacol Sci, 2011, 115(3), 329-335.

Sigma Aldrich - PZ0104

Biochem/physiol Actions
CP-91149 is a selective glycogen phosphorylase inhibitor.
Legal Information
Sold for research purposes under agreement from Pfizer Inc.

Toronto Research Chemicals - C781355

A potent and selective PPARα agonist. It exhibits hypolipidemic activity in vivo.

REFERENCES

• Martin WH, et al. Proc Natl Acad Sci U S A, 1998, 95(4), 1776-1781.
• Aiston S, et al. J Biol Chem, 2001, 276(26), 23858-23866.
• Schnier JB, et al. Biochem Biophys Res Commun, 2003, 309(1), 126-134.
• Lerín C, et al. Biochem J, 2004, 378(Pt 3), 1073-1077.
• Yoshida T, et al. J Pharmacol Sci, 2011, 115(3), 329-335.
• Kane, C.D. et al.: Mol. Pharmacol., 75, 296, (2009)