GSK256066

Catalog No.S2620

GSK256066 is a selective PDE4B(equal affinity to isoforms A-D) inhibitor with IC50 of 3.2 pM, >380,000-fold selectivity versus PDE1/2/3/5/6 and >2500-fold selectivity against PDE4B versus PDE7.Phase 2.

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GSK256066 Chemical Structure

GSK256066 Chemical Structure
Molecular Weight: 518.58

Validation & Quality Control

Quality Control & MSDS

Related Compound Libraries

GSK256066 is available in the following compound libraries:

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  • GSK256066 Mechanism

Product Description

Biological Activity

Description GSK256066 is a selective PDE4B(equal affinity to isoforms A-D) inhibitor with IC50 of 3.2 pM, >380,000-fold selectivity versus PDE1/2/3/5/6 and >2500-fold selectivity against PDE4B versus PDE7.Phase 2.
Targets PDE4B [1]
IC50 3.2 pM
In vitro GSK256066 is a slow and tight binding inhibitor of PDE4B with apparent IC50 of 3.2 pM. GSK256066 is an extremely potent inhibitor of LPS-stimulated TNFα production in PBMCs with pIC50 of 11.0 and IC50 of 10 pM and human whole-blood cultures with pIC50 of 9.90 and IC50 of 126 pM. GSK256066 is highly selective for PDE4 (>3.8 × 105-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2.5 × 103-fold against PDE7). GSK256066 inhibits PDE4 isoforms A-D with equal affinity. [1]
In vivo GSK256066 inhibits the LPS-induced pulmonary neutrophilia with an ED50 of 1.1 μg/kg, achieving maximal inhibition of 72% at 30 μg/kg when given in the aqueous suspension. GSK256066 inhibits the LPS-induced pulmonary neutrophilia with ED50 of 2.9 μg/kg, achieving maximal inhibition of 62% when given in the dry powder formulation. GSK256066 shows a moderate plasma clearance of 39 ml/min/kg, a moderate volume of distribution of 0.8 L/kg, and a relatively short half-life of 1.1 hour in the male CD rat. [1] GSK256066 sustains at a high lung concentration of 2.6 μg/g after intra-tracheal administration as an aqueous suspension at a dose of 30 μg/kg in rats. [2] GSK256066 (10 μg/kg) is administered intratracheally at different times (2, 6, 12, 18, 24, and 36 hours) before LPS administration, inhibiting LPS-Induced Pulmonary Neutrophilia in rat lipopolysaccharide (LPS)-induced models of acute pulmonary inflammation. GSK256066 (0.3–100 μg/kg) inhibits LPS-induced increases in exhaled nitric oxide with ED50 of 35 μg/kg in rat. GSK256066 (10 μg/kg) is administered half a hour before OVA administration in rat, inhibiting OVA-induced pulmonary eosinophilia with ED50 of 0.4 μg/kg. GSK256066 administered intratracheally as a dry powder blended in respiratory-grade lactose at doses of 3 to 100 μg/kg 2 hours before inhaled LPS challenge in ferrets, inhibiting LPS-induced pulmonary neutrophilia with ED50 of 18 μg/kg without inducing emetic episodes. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

SPA assays and fluorescence polarization assays For SPA assays, 75 μL of PDE enzyme in 50 mM Tris-HCl, pH 7.5, containing 8.3 mM MgCl2, 1.7 mM EGTA, and 0.05% (w/v) BSA is preincubated with 2 μL of GSK256066 solution or DMSO for 30 min. For PDE1 assays the assay buffer containes additionally 4 μg/mL calmodulin and 1 mM CaCl2 and does not contain any EGTA. Assays are initiated by the addition of 25 μL of [3H]cAMP (10 nM final concentration: PDE3, PDE4, and PDE7) or [3H]cGMP (36 nM: PDE1, PDE2, PDE5, and PDE6). After a 1 hour incubation, assays are terminated by addition of 50 μL of aqueous suspension of SPA beads (approximately 1 mg per well) and, after an incubation of at least 30 min, bound radioactivity is measured by liquid scintillation counting. For fluorescence polarization assays, 10 μL of PDE enzyme in 10 mM Tris-HCl buffer, pH 7.2, containing 10 mM MgCl2, 0.1% (w/v) BSA, and 0.05% (w/v) NaN3 is preincubated with 0.5 μL of inhibitor or DMSO for 30 min. Assays are initiated by the addition of 10 μL of fluorescein-cAMP (40 nM final concentration) and terminated after 40 min by the addition of 60 μL of IMAP binding reagent (1 in 400 dilution of stock suspension in binding buffer). The ratio of parallel to perpendicular light is measured using an Analyst or Aquest plate reader.

Animal Study: [1]

Animal Models Male CD rats
Formulation Sterile 0.9% sodium chloride solution
Dosages 0.1–100 μg/kg
Administration Administered intratracheally as an aqueous suspension or a dry powder 2 h before LPS challenge.

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] Tralau-Stewart CJ, et al. J Pharmacol Exp Ther, 2011, 337(1), 145-154.

[2] Woodrow MD, et al. Bioorg Med Chem Lett, 2009, 19(17), 5261-5265.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00612118 Completed Allergic Rhinitis|Rhinitis, Allergic, Seasonal GlaxoSmithKline February 2008 Phase 2
NCT00612820 Completed Allergic Rhinitis|Rhinitis, Allergic, Seasonal GlaxoSmithKline January 2008 Phase 2
NCT00549744 Completed Asthma|Mild Asthma GlaxoSmithKline November 2007 Phase 2
NCT00549679 Completed Pulmonary Disease, Chronic Obstructive GlaxoSmithKline October 2007 Phase 2
NCT00515268 Completed Pulmonary Disease, Chronic Obstructive|Healthy Subjects GlaxoSmithKline September 2007 Phase 1

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Chemical Information

Download GSK256066 SDF
Molecular Weight (MW) 518.58
Formula

C27H26N4O5S

CAS No. 801312-28-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 5 mg/mL (9.64 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 mg/mL
* <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 6-(3-(dimethylcarbamoyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylquinoline-3-carboxamide

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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