product name GSK256066
Description: GSK256066 is a potent and selective PDE4B inhibitor with IC50 of 3.2 pM, it has >380,000-fold selectivity versus PDE1/2/3/5/6 and >2500-fold selectivity against PDE4B versus PDE7. GSK256066 can be given by inhalation which can minimize the potential for side effects. It demonstrated a protective effect on the EAR and LAR. GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for chronic obstructive pulmonary disease.
References: J Pharmacol Exp Ther. 2011 Apr;337(1):145-54; J Pharmacol Exp Ther. 2011 Apr;337(1):137-44.
518.58
Formula
C27H26N4O5S
CAS No.
801312-28-7
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 5 mg/mL (9.6 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL
Synonyms
other peoduct :
| In Vitro |
In vitro activity: 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. Kinase Assay: Cell Assay: |
|---|---|
| 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. 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. 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. |
| Animal model | Male CD rats |
| Formulation & Dosage | Dissolved in 0.9% sodium chloride solution; 0.1–100 μg/kg; Administered intratracheally as an aqueous suspension or a dry powder 2 h before LPS challenge. |
| References | J Pharmacol Exp Ther. 2011 Apr;337(1):145-54; Bioorg Med Chem Lett. 2009 Sep 1;19(17):5261-5; J Pharmacol Exp Ther. 2011 Apr;337(1):137-44. |
