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860352-01-8 molecular structure
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3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide

ChemBase ID: 72731
Molecular Formular: C17H19FN4O2S
Molecular Mass: 362.4217632
Monoisotopic Mass: 362.12127509
SMILES and InChIs

SMILES:
c1(cccc(c1)c1sc(c(c1)NC(=O)N)C(=O)N[C@@H]1CNCCC1)F
Canonical SMILES:
NC(=O)Nc1cc(sc1C(=O)N[C@H]1CCCNC1)c1cccc(c1)F
InChI:
InChI=1S/C17H19FN4O2S/c18-11-4-1-3-10(7-11)14-8-13(22-17(19)24)15(25-14)16(23)21-12-5-2-6-20-9-12/h1,3-4,7-8,12,20H,2,5-6,9H2,(H,21,23)(H3,19,22,24)/t12-/m0/s1
InChIKey:
IAYGCINLNONXHY-LBPRGKRZSA-N

Cite this record

CBID:72731 http://www.chembase.cn/molecule-72731.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide
IUPAC Traditional name
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide
Synonyms
AZD7762
CAS Number
860352-01-8
PubChem SID
162037652
PubChem CID
11152667

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1532 external link Add to cart Please log in.
Data Source Data ID
PubChem 11152667 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 11.59091  H Acceptors
H Donor LogD (pH = 5.5) -0.77325773 
LogD (pH = 7.4) 0.3070208  Log P 2.4024029 
Molar Refractivity 95.535 cm3 Polarizability 36.65545 Å3
Polar Surface Area 96.25 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

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

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S1532 external link
Research Area
Description Solid tumours
Biological Activity
Description AZD7762 is a novel CHK1 and CHK2 inhibitor with IC50 of 5 nM and <10 nm,="">
Targets CHK1 CHK2
IC50 5 nM [1] <10 nm="">[1]
In Vitro AZD7762, a more selective Chk1 inhibitor, inhibits Chk1 phosphorylation of a cdc25C peptide by reversibly binding to the ATP-binding site of Chk1, with IC50 of 5 nM and Ki of 3.6 nM. AZD7762 induces cell arrest with EC50 of 0.620 μM, and significantly abrogates the camptothecin induced G2 arrest with an EC50 of 10 nM, by blocking the chk1 dependent degradation of Cdc25A and activation of Cyclin A. AZD7762 (300 nM) enhances the antitumor efficacy of gemcitabine against SW620 and topotecan against MDA-MB-231 by reducing the GI50 values from 24.1 nM and 2.25 μM to 1.08 nM and 0.15 μM, respectively. [1] AZD7762 shows cytotoxicity against a variety of neuroblastoma cell lines bearing p53 wild type, p53 mutation, Mdm2 amplification or p14 deletion with IC50 values ranging from 82.6-505.9 nM. [2]
In Vivo AZD7762 alone at 25 mg/kg shows little antitumor activity in the H460-DNp53 xenograft mice and SW620 xenograft mice, but when administrated in combination with gemcitabine (60 mg/kg), AZD7762 shows significant antitumor efficacy in the two xenografts mice with a log cell kill of 0.9 or percent treated/control (%T/C) of 26 even at low dose of 12.5 mg. Dosing of AZD7762 in combination with gemcitabine (10 mg/kg) in the H460-DNp53 xenograft rat inhibits the tumor volume in a dose-dependent manner with the %T/C values of 48 and 32 for 10 and 20 mg/kg AZD7762, respectively. AZD7762 (25 mg/kg) in combination with irinotecan (25 or 50 mg/kg) causes complete tumor regression in the SW620 xenograft mice with the %T/C increasing significantly to -66% and -67%, respectively. [1]
Clinical Trials A Phase I study to assess safety of AZD7762 administered alone and in combination with gemcitabine in patients with advanced solid malignancies has been completed.
Features
Protocol
Kinase Assay [1]
Chk1 Kinase Assay Recombinant human Chk1 is expressed as a glutathione S-transferase fusion in insect cells using a baculovirus vector and purified by glutathione affinity chromatography. A synthetic peptide substrate (N-biotinylaminohexanoyl-KKVSRSGLYRSPMPENLNRPR) for Chk1 is synthesized. Final assay concentrations of peptide and ATP (cold + 40 nCi [33P]ATP) are 0.8 and 1 μM, respectively. Different concentrations of AZD7762, buffer containing peptide and chk1 kinase and ATP, are added sequentially to a 384-well assay plate. The plate is incubated for 2 hours, reaction is stopped by the addition of buffer containing EDTA and scintillation proximity assay beads, and plates are read using a TopCount reader. Data analysis is carried out to determinate a dose response (IC50).
Cell Assay [1]
Cell Lines HT29, SW620 and MDA-MB-231 cells
Concentrations Dissolved in DMSO, final concentration ~12.5 μM
Incubation Time 20 or 48 hours
Methods For the checkpoint abrogation assay, HT29 cells are treated for 2 hours with camptothecin (topoisomerase I inhibitor; 0.07 μg/mL) to induce the G2 checkpoint. Cells are then treated for 20 hours with a 12-point titration of AZD7762 (12.5 μM to 6 nM) plus nocodazole. Cells are fixed with 3.7% formaldehyde for 1 hour, permeabilized with PBS containing 0.05% Triton X, and incubated with anti-phH3 antibody for 1 hour followed by Alexa Fluor 488 anti-rabbit and Hoechst stain for 1 hour. Mitotic index is determined on the ArrayScan and expressed as the percentage of cells undergoing mitosis. For the potentiation assays, SW620 or MDA-MB-231 cells are dosed for 24 hours with a 9-point titration of gemcitabine ranging from 0.01 to 100 nM with a constant dose of AZD7762 (300 nM). After 24 hours, medium is removed and AZD7762 alone is added back to the wells for an additional 24 hours. Cells are then incubated in AZD7762-free medium for an additional 72 hours. The effect on cell proliferation is determined by MTT.
Animal Study [1]
Animal Models Male NCr mice implanted s.c. with H460-DNp53 cells or SW620, and male rnu rats implanted s.c. with H460-DNp53 cells
Formulation Formulated in 11.3% hydroxyproplyl-β-cyclodextrin
Doses ~25 mg/kg
Administration Injection i.v.
References
[1] Zabludoff SD, et al. Mol Cancer Ther, 2008, 7(9), 2955-2966.

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