3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine

• ChemBase ID: 6303
• Molecular Formular: C21H22Cl2FN5O
• Molecular Mass: 450.3366832
• Monoisotopic Mass: 449.11854393
• SMILES: Clc1ccc(F)c(c1[C@@H](C)Oc1cc(cnc1N)c1cnn(c1)C1CCNCC1)Cl
• Canonical SMILES: Nc1ncc(cc1O[C@@H](c1c(Cl)ccc(c1Cl)F)C)c1cnn(c1)C1CCNCC1
• InChI: InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
• InChIKey: KTEIFNKAUNYNJU-GFCCVEGCSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
• IUPAC Traditional name: crizotinib
• Synonyms: 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-amine; (R)-3-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; PF-02341066; Crizotinib; PF-2341066; (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine; PF 2341066; PF02341066; Xalkori; Crizotinib

Database IDs

• CAS Number: 877399-52-5
• MDL Number: MFCD12407409
• PubChem SID: 160969694
• PubChem CID: 11626560

CALCULATED PROPERTIES

JChem

• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): -0.118933685
• LogD (pH = 7.4): 0.9544419
• Log P: 3.5741167
• Molar Refractivity: 128.4316 cm^3
• Polarizability: 45.653618 Å^3
• Polar Surface Area: 77.99 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 3.82
• LOG S: -4.87
• Solubility (Water): 6.11e-03 g/l

PROPERTIES

Physical Property

• Solubility: DMSO
• Apperance: white to tan powder

Safety Information

• Storage Condition: -20°C
• Storage Warning: IRRITANT
• TSCA Listed: false
• Storage Temperature: room temp

Pharmacology Properties

• Target: ALK; c-Met

Product Information

• Purity: ≥98% (HPLC); 95%
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C21H22Cl2FN5O

DETAILS

DrugBank - DB08700

Drug information: experimental

Selleck Chemicals - S1068

Research Area

• Description: Cancer

Protocol

• Protocol: Kinase Assay ^[1]
• Biochemical kinase assays: c-Met catalytic activity is quantitated using a continuous-coupled spectrophotometric assay in which the time-dependent production of ADP by c-Met is determined by analysis of the rate of consumption of NADH. NADH consumption is measured by a decrease in absorbance at 340 nm by spectrophotometry at designated time points. To determine K_i values, PF-2341066 is introduced into test wells at various concentrations in the presence of assay reagents and incubated for 10 minutes at 37 °C. The assay is initiated by the addition of the c-Met enzyme.
• Protocol: Cell Assay ^[1]
• Cell Lines: GTL-16 gastric carcinoma cells and T47D breast carcinoma cells
• Concentrations: 0-256 nM
• Incubation Time: 1 hour
• Methods: Cells including GTL-16 gastric carcinoma cells and T47D breast carcinoma cells are seeded in 96-well plates in media supplemented with 10% fetal bovine serum (FBS) and transferred to serum-free media [with 0.04% bovine serum albumin (BSA)] after 24 hours. In experiments investigating ligand-dependent RTK phosphorylation, corresponding growth factors are added for up to 20 minutes. After incubation of cells with PF-2341066 for 1 hour and/or appropriate ligands for the designated times, cells are washed once with HBSS supplemented with 1 mM Na₃VO₄, and protein lysates are generated from cells. Subsequently, phosphorylation of selected protein kinases is assessed by a sandwich ELISA method using specific capture antibodies used to coat 96-well plates and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are (a) incubated in the presence of protein lysates at 4 °C overnight; (b) washed seven times in 1% Tween 20 in PBS; (c) incubated in a horseradish peroxidase–conjugated anti–total-phosphotyrosine (PY-20) antibody (1:500) for 30 min; (d) washed seven times again; (e) incubated in 3,3^′,5,5^′-tetramethyl benzidine peroxidase substrate to initiate a colorimetric reaction that is stopped by adding 0.09 N H₂SO₄; and (f) measured for absorbance in 450 nm using a spectrophotometer.
• Protocol: Animal Study ^[1]
• Animal Models: Female or male nu/nu mice bearing NCI-H441,or DLD-1, or MDA-MB-231
• Doses: 12.5 mg/kg/day, 25 mg/kg/day, and 50 mg/kg/day
• Administration: Administered via p.o.

References

• References: [1] Zou HY, et al. Cancer Res. 2007, 67(9), 4408-4417.
• References: [2] Christensen JG, et al. Mol Cancer Ther. 2007, 6(12 Pt 1), 3314-3322.
• References: [3] Sampson ER, et al. J Bone Miner Res. 2011, 26(6), 1283-1294.
• References: [4] Cullinane C, et al. J Nucl Med. 2011, 52(8), 1261-1267.
• References: [5] Gong HC, et al. Int J Proteomics. 2011, 2011, 215496.

Sigma Aldrich - PZ0191

Legal Information
Sold for research purposes under agreement from Pfizer Inc.
Biochem/physiol Actions
Crizotinib (PF-02341066) is an ATP-competitive inhibitor of the receptor tyrosine kinases (RTKs) c-Met (hepatocyte growth factor receptor) and anaplastic lymphoma kinase (ALK). It is a highly specific inhibitor of c-Met and ALK among > 120 different RTKs surveyed. Crizotinib was recently approved for treatment of a subtype of nonsmall-cell lung cancer (NSCLC) with ALK fusion mutations.

REFERENCES

• Zou HY, et al. Cancer Res. 2007, 67(9), 4408-4417.
• Christensen JG, et al. Mol Cancer Ther. 2007, 6(12 Pt 1), 3314-3322.
• Sampson ER, et al. J Bone Miner Res. 2011, 26(6), 1283-1294.
• Cullinane C, et al. J Nucl Med. 2011, 52(8), 1261-1267.
• Gong HC, et al. Int J Proteomics. 2011, 2011, 215496.