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857531-00-1 molecular structure
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4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine

ChemBase ID: 5492
Molecular Formular: C20H20ClN3
Molecular Mass: 337.8459
Monoisotopic Mass: 337.13457534
SMILES and InChIs

SMILES:
Clc1ccc(cc1)C1(CCNCC1)c1ccc(cc1)c1c[nH]nc1
Canonical SMILES:
Clc1ccc(cc1)C1(CCNCC1)c1ccc(cc1)c1c[nH]nc1
InChI:
InChI=1S/C20H20ClN3/c21-19-7-5-18(6-8-19)20(9-11-22-12-10-20)17-3-1-15(2-4-17)16-13-23-24-14-16/h1-8,13-14,22H,9-12H2,(H,23,24)
InChIKey:
LZMOSYUFVYJEPY-UHFFFAOYSA-N

Cite this record

CBID:5492 http://www.chembase.cn/molecule-5492.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine
IUPAC Traditional name
4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine
Synonyms
4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE
AT7867
CAS Number
857531-00-1
PubChem SID
160968920
99444330
PubChem CID
11175137

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1558 external link Add to cart Please log in.

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem ALOGPS 2.1
Acid pKa 14.632122  H Acceptors
H Donor LogD (pH = 5.5) 0.8478351 
LogD (pH = 7.4) 1.5398964  Log P 4.067616 
Molar Refractivity 110.1719 cm3 Polarizability 39.505894 Å3
Polar Surface Area 40.71 Å2 Rotatable Bonds
Lipinski's Rule of Five true 
Log P 4.46  LOG S -5.6 
Solubility (Water) 8.43e-04 g/l 

PROPERTIES

PROPERTIES

Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Target
Akt expand Show data source
S6 kinase expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

DrugBank DrugBank Selleck Chemicals Selleck Chemicals
DrugBank - DB07859 external link
Drug information: experimental
Selleck Chemicals - S1558 external link
Research Area
Description Cancer
Biological Activity
Description AT7867 is a potent ATP-competitive inhibitor of Akt1, Akt2 and Akt3 with IC50 of 32 nM, 17 nM and 47 nM, respectively.
Targets Akt1 Akt2 Akt3
IC50 32 nM 17 nM 47 nM [1]
In Vitro AT7867 also inhibits structurally related AGC kinases p70S6K and PKA with IC50 of 20 nM and 85 nM, respectively. AT7867 shows ATP-competitive activity to Akt2 with Ki of 18 nM. AT7867 exhibits antiproliferation in cell lines with PTEN or PIK3CA mutations and shows great potent to MES-SA, MDA-MB-468, MCF-7, HCT116 and HT29 with IC50 of 0.94 μM, 2.26 μM, 1.86 μM, 1.76 μM and 3.04 μM, respectively. AT7867 also suppresses the cell growth of U87MG, PC-3 and DU145 cells with IC50 of 8.22 μM, 10.37 μM and 11.86 μM, respectively. AT7867 suppresses Akt activity by inhibiting phosphorylation of GSK-3β in human tumor cells with IC50 of 2-4 μM. AT7867 also induces the phosphorylation of the following Akt direct substrates including proapoptotic transcription factors FKHR (FoxO1a), FKHRL1 (FoxO3a) and the downstream target S6RP in U87MG cells. [1]
In Vivo AT7867 shows bioavailability of 44% in mice by p.o. route. AT7867 could increase the cleaved PARP in MES-SA xenografts at 20 mg/kg i.p. or 90 mg/kg p.o.. AT7867 significantly inhibits the tumor growth in MES-SA xenografts or U87MG xenografts with T/C of 0.37 and 0.51, respectively. [1]
Clinical Trials
Features
Protocol
Kinase Assay [1]
In vitro kinase assays Kinase assays for Akt2, PKA, p70S6K, and CDK2/cyclin A are all carried out in a radiometric filter binding format. Assay reactions are set up in the presence of AT7867. For Akt2, the Akt2 enzyme and 25 μM Aktide-2T peptide (HARKRERTYSFGHHA) are incubated in 20 mM MOPS (pH 7.2), 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 10 μg/mL bovine serum albumin, and 30 μM ATP (1.16 Ci/mmol) for 4 hours. For PKA, the PKA enzyme and 50 μMpeptide (GRTGRRNSI) are incubated in 2 mM MOPS (pH 7.2), 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM orthovanadate, 1 mM DTT, and 40 μM ATP (0.88 Ci/mmol) for 20 minutes. For p70S6K, the p70S6K enzyme and 25 μMpeptide substrate (AKRRRLSSLRA) are incubated in 10 mM MOPS (pH 7), 0.2 mM EDTA, 1 mM MgCl2, 0.01% β-mercaptoethanol, 0.1 mg/mL bovine serum albumin, 0.001% Brij-35, 0.5% glycerol, and 15 μM ATP (2.3 Ci/mmol) for 60 min. For CDK2, the CDK2/cyclin A enzyme and 0.12 μg/mL histone H1 are incubated in 20 mM MOPS (pH 7.2), 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 0.1 mg/mL bovine serum albumin, and 45 μM ATP (0.78 Ci/mmol) for 4 hours. Assay reactions are stopped by adding an excess of orthophosphoric acid, and the stopped reaction mixture is then transferred to Millipore MAPH filter plates and filtered. The plates are then washed, scintillant is added, and radioactivity is measured by scintillation counting on a Packard TopCount. IC50 values are calculated from replicate curves using GraphPad Prism software. Akt1 and Akt3 enzyme assays are carried out.
Cell Assay [1]
Cell Lines MES-SA, MDA-MB-468, MCF-7, HCT116, HT29, U87MG, PC-3 and DU145 cells
Concentrations 0-100 μM , dissolved to a 10 mM stock in DMSO
Incubation Time 72 hours
Methods Cells are plated in 96-well microplates at 5 × 103 per well in medium supplemented with 10% fetal bovine serum and grown for 24 hours before treatment with AT7867. AT7867 or vehicle control is added to the cells for 72 hours. Following this, Alamar Blue solution is added. The IC50 value for AT7868 is calculated in GraphPad Prism using nonlinear regression analysis and a sigmoidal dose-response (variable slope) equation.
Animal Study [1]
Animal Models Human MES-SA uterine sarcoma cells or U87MG human glioblastoma cells are injected s.c. in the right flank of BALB/c mice.
Formulation Formulated in a vehicle containing 10% DMSO, 20% water, and 70% hydroxypropyl-β-cyclodextrin (25% aqueous, w/v)
Doses 20 mg/kg (i.p.) or 90 mg/kg (p.o.) once every 3 days
Administration Administered via i.p. or p.o.
References
[1] Grimshaw KM, Mol Cancer Ther, 2010, 9(5), 1100-1110.

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