GSK256066 is a selective phosphodiesterase 4 (PDE4)inhibitor with an IC50 of 3.2 pM. Oral phosphodiesterase (PDE)4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical andclinical investigation of inhaled PDE4 inhibitors is ongoing. GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast.GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease.
|Source||J Pharmacol Exp Ther (2011). Figure 3. GSK256066|
|Incubation Time||6 h|
|Results||GSK256066 and FP inhibited the increase in eosinophil number in the BAL in a dose-dependent fashion|
|Cell lines||PBMCs cells line|
|Preparation method||Compound Preparation for In Vitro Assays.
Dilution series for pIC50 determinations generally comprised eight successive 3-fold dilutions in DMSO. Low-volume additions (0.5-2.0 μl) to assays were carried out using a Biomek Fx liquid-handling robot (Beckman Coulter, Fullerton, CA).Percentages of inhibition values were generated relative to uninhibited controls. Values for pIC50 were determined from concentration-response curves by nonlinear least-squares curve fitting, in general using a four-parameter logistic equation in Activity Base (IDBS, Guildford, Surrey, UK).
|Incubation time||72 h|
|Animal models||LPS-induced pulmonary neutrophilia in rats model|
|Formulation||0.2% Tween 80 in normal saline|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO 5 mg/mL|
In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor.
Nials et al. J Pharmacol Exp Ther. 2011 Apr;337(1):137-44. PMID: 21205924.
GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization.
Tralau-Stewart et al. J Pharmacol Exp Ther. 2011 Apr;337(1):145-54. PMID: 21205923.
The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma.
Singh et al. Respir Res. 2010 Mar 1;11:26. PMID: 20193079.
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