GSK256066

ArtNr	S2620-10000
Hersteller	Selleckchem
CAS-Nr.	801312-28-7
Menge	10 g
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 50 mg 5 g
Kategorie	Oncology Neuroscience Molecular Targets for Neuroscience Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer
Typ	Inhibitors
Specific against	other
Smiles	CC1=CC(=CC2=C(C(=CN=C12)C(=O)N)NC3=CC(=CC=C3)OC)S(=O)(=O)C4=CC=CC(=C4)C(=O)N(C)C
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	801312-28-7'
Similar products	GSK256066
Lieferbar
Manufacturer - Targets	PDE4B
Storage Conditions	2 years -80 in solvent
Molecular Weight	518, 58
Administration	Administered intratracheally as an aqueous suspension or a dry powder 2 h before LPS challenge.
Animal Models	Male CD rats
Clinical Trials	GSK256066 is currently in phase II clinical trials for Chronic Obstructive Pulmonary Disease (COPD)
Dosages	0.1â€“100 ug/kg
Formulation	Sterile 0.9% sodium chloride solution
IC50	3.2 pM [1], 3.2 pM [1], 3.2 pM [1], 3.2 pM [1], 3.2 pM [1], 3.2 pM [1]
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 TNFalpha 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 ug/kg, achieving maximal inhibition of 72% at 30 ug/kg when given in the aqueous suspension. GSK256066 inhibits the LPS-induced pulmonary neutrophilia with ED50 of 2.9 ug/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 ug/g after intra-tracheal administration as an aqueous suspension at a dose of 30 ug/kg in rats. [2] GSK256066 (10 ug/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 (0.3â€“100 ug/kg) inhibits LPS-induced increases in exhaled nitric oxide with ED50 of 35 ugg in rat. GSK256066 (10 ug/kg) is administered half a hour before OVA administration in rat, inhibiting OVA-induced pulmonary eosinophilia with ED50 of 0.4 ug/kg. GSK256066 administered intratracheally as a dry powder blended in respiratory-grade lactose at doses of 3 to 100 ug/kg 2 hours before inhaled LPS challenge in ferrets, inhibiting LPS-induced pulmonary neutrophilia with ED50 of 18 ug/kg without inducing emetic episodes. [3]
Kinase Assay	SPA assays and fluorescence polarization assays, For SPA assays, 75 uL 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 uL of GSK256066 solution or DMSO for 30 min. For PDE1 assays the assay buffer containes additionally 4 ug/mL calmodulin and 1 mM CaCl2 and does not contain any EGTA. Assays are initiated by the addition of 25 uL 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 uL 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 uL 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 uL of inhibitor or DMSO for 30 min. Assays are initiated by the addition of 10 uL of fluorescein-cAMP (40 nM final concentration) and terminated after 40 min by the addition of 60 uL 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.
Solubility (25C)	DMSO 5 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	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.
Chemical Name	6-(3-(dimethylcarbamoyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylquinoline-3-carboxamide

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