PF-2545920

Catalog No.S2687

PF-2545920 is a potent and selective PDE10A inhibitor with IC50 of 0.37 nM, with >1000-fold selectivity over the PDE.

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PF-2545920 Chemical Structure

PF-2545920 Chemical Structure
Molecular Weight: 392.45

Validation & Quality Control

2 customer reviews :

Quality Control & MSDS

Related Compound Libraries

PF-2545920 is available in the following compound libraries:

Product Information

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  • PF-2545920 Mechanism

Product Description

Biological Activity

Description PF-2545920 is a potent and selective PDE10A inhibitor with IC50 of 0.37 nM, with >1000-fold selectivity over the PDE.
Targets PDE10A [2]
IC50 0.37 nM
In vitro PF-2545920 shows excellent potency and selectivity of PDE10A with IC50 of 1.26 nM. [1]
In vivo PF-2545920 intraperitoneally administrated at dose of 0.3, 3, and 5 mg/kg in male CF-1 mice causes striking increases in GluR1 phosphorylation levels of 3-, 5.4-, and 4.1-fold , respectively. MP-10 at concentration of 1 μM treats Rat striatal slices for 30 min, the level of GluR1S845 phosphorylation at the cell surface is significantly increased 2-fold, without change the level of total GluR1 on the cell surface. MP-10 intraperitoneally administrated at dose of 0.3, 3, and 5 mg/kg in male CF-1 mice results in robust, statistically significant increases in CREBS133 phosphorylation of 3-, 4-, and 2.6-fold, respectively. MP-10 intraperitoneally administrated at dose of 3 mg/kg increases both enkephalin and substance-P mRNA levels in striatum of CF-1 mice. MP-10 intraperitoneally administrated at dose of 0.3-1 mg/kg decreases avoidance responding with a significant treatment effect in the mouse CAR model. Mice treated with MP-10 at dose of 0.03 mg/kg spents more time in the empty than social side in the mice, MP-10 also dose-dependently decreased locomotor activity. [1] PDE10A subcutaneously administrated at dose of 1 mg/kg elevates striatal cGMP about 3 fold in male CD-1 mice, while PDE10A subcutaneously administrated at dose of 3.2 mg/kg displays a maximal elevation of striatal cGMP approximately a 5-fold increase in male CD-1 mice. PDE10A intravenous injected at a dose of 0.1 mg/kg in Sprague-Dawley rats displays clearance of 36 ml/min/Kg, DE10A intravenous injected at a dose of 0.3 mg/kg in Dog Beagle displays clearance of 7.2 ml/min/Kg in vivo clearance with a moderate volume of distribution, DE10A intravenous injected at a dose of 0.03 mg/kg in Monkey Cynomolgus displays clearance of 13.9 ml/min/Kg in vivo clearance with a moderate volume of distribution. PDE10A is active with an ED50 of 1 mg/kg at a significantly lower total plasma exposure (115 nM) in the conditioned avoidance response assay (CAR) in Sprague-Dawley rats. [2]
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

PDE10 enzyme assay PDE10A is generated from the full-length recombinant rat clone transfected into Sf9 cells. The enzyme is extracted from cell pellets in lysis buffer (20 mM Tris, 2 mM benzamidine, 1.0 mM Na2EDTA, 0.25 M sucrose, 100 μM PMSF, pH 7.5 at room temperature) and stored frozen at -80 °C. PDE activity is measured using a plate based Scintillation Proximity Assay (SPA) modified from an Amersham Biosciences protocol. The Km of the PDE10A preparation is experimentally determined to be 24 nM at room temperature. For competitive enzyme inhibition assays, the substrate [3H]cAMP concentration is held at 20 nM for conditions to be at or below the Km of the enzyme. The concentration of enzyme is adjusted to convert less than 10% of available substrate to end product during the assay. PF-2545920 is initially dissolved in DMSO and diluted such that the final DMSO assay concentration is 3%. Following the addition of the test agents and [3H]-cAMP, enzyme is added in buffer containing 50 mM Tris and 1.3 mM MgCl2 (pH 7.5) to a final volume of 50 ul. The incubation is allowed to proceed for 30 min at room temperature before the addition of 20 ul of PDE SPA beads at 0.2 mg/well to stop the reaction. Plates are allowed to stand 10 to 12 hours before counting in a Trilux plate reader. IC50s are calculated after the subtraction of background as determined by addition of 10 uM papaverine.

Animal Study:

[2]

Animal Models Jugular vein-cannulated male Sprague-Dawley rats
Formulation 5:5:90 DMSO:1N HCl:saline
Dosages 0.1 mg/kg
Administration Inject intravenous through jugular vein catheter in a single dose 4 hours before feed

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Grauer SM, et al. J Pharmacol Exp Ther, 2009, 331(2), 574-590.

[2] Verhoest PR, et al. J Med Chem, 2009, 52(16), 5188-5196.

Chemical Information

Download PF-2545920 SDF
Molecular Weight (MW) 392.45
Formula

C25H20N4O

CAS No. 1292799-56-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 78 mg/mL warming (198.75 mM)
Ethanol 78 mg/mL (198.75 mM)
Water <1 mg/mL (<1 mM)
In vivo
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline

Customer Product Validation(2)


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Rating
Source Oncogene 2014 10.1038/onc.2014.94. PF-2545920 purchased from Selleck
Method Western blot
Cell Lines HT29 cells
Concentrations 0-20 uM
Incubation Time 24 h
Results Pf-2545920 increased the activity of caspase-3 and 7 and inhibited DNA synthesis in a dose-dependent mannerwithin the same concentration range as its IC 50 value for inhibitingcolon tumor cell growth.

Click to enlarge
Rating
Source Oncogene 2014 10.1038/onc.2014.94. PF-2545920 purchased from Selleck
Method luciferase-based ATP assay
Cell Lines NCM460, HT29, SW480 and HCT116 cells
Concentrations 0-100 Um
Incubation Time 72 h
Results The PDE10 inhibitor Pf-2545920 suppressed the growth of human NCM460, HT29, SW480 and HCT116 colon tumor cell lines by greater than 90% with IC 50 values ranging from 0.1 - 28 μ mol/l.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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