GSK256066

Apparent IC50 3.2 pM, steady state IC50 < 0.5 pM

GSK256066 is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery.

Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma.

In vitro: GSK256066 is a slow- and tight-binding inhibitor of PDE4B, more potent than any previously documented compound, for example roflumilast, tofimilast and cilomilast [1].

In vivo: When administered by the intratracheal route to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED50s of 1.1 μg/kg (aqueous suspension) and 2.9 μg/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED50 9.3 μg/kg) [1].

Clinical trial: Administration of inhaled GSK256066 was well-tolerated in patients with moderate COPD. Further studies would be required to confirm the favorable safety profile and to demonstrate clinical efficacy of this compound [2].

References:
[1] Tralau-Stewart CJ, Williamson RA, Nials AT, Gascoigne M, Dawson J, Hart GJ, Angell AD, Solanke YE, Lucas FS, Wiseman J, Ward P, Ranshaw LE, Knowles RG.  GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. J Pharmacol Exp Ther. 2011;337(1):145-54.
[2] Watz H, Mistry SJ, Lazaar AL; IPC101939 investigators.  Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulm Pharmacol Ther. 2013;26(5):588-95.

GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization.[Pubmed:21205923]

J Pharmacol Exp Ther. 2011 Apr;337(1):145-54.

Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and we describe 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy) phenyl]amino}-3-quinolinecarboxamide (GSK256066), an exceptionally high-affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slow and tight binding inhibitor of PDE4B (apparent IC(50) 3.2 pM; steady-state IC(50) <0.5 pM), which is more potent than any previously documented compound, for example, roflumilast (IC(50) 390 pM), tofimilast (IC(50) 1.6 nM), and cilomilast (IC(50) 74 nM). Consistent with this, GSK256066 inhibited tumor necrosis factor alpha production by lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes with 0.01 nM IC(50) (compared with IC(50) values of 5, 22, and 389 nM for roflumilast, tofimilast, and cilomilast, respectively) and by LPS-stimulated whole blood with 126 pM IC(50). GSK256066 was highly selective for PDE4 (>380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (>17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED(50) values of 1.1 mug/kg (aqueous suspension) and 2.9 mug/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED(50) 9.3 mug/kg). Thus, 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.

In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor.[Pubmed:21205924]

J Pharmacol Exp Ther. 2011 Apr;337(1):137-44.

Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]a mino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)- and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p < 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 x ED(50) dose (10 mug/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED(50) 35 and 92 mug/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED(50) 0.4 mug/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED(50) 18 mug/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, 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.

Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD.[Pubmed:23701917]

Pulm Pharmacol Ther. 2013 Oct;26(5):588-95.

BACKGROUND: Inhibition of phosphodiesterase 4 (PDE4) represents an approach to anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). GSK256066 is a potent and selective inhaled PDE4 inhibitor. The aim of this study was to investigate the safety and tolerability of 28 days repeat inhaled dosing with GSK256066 in moderate COPD. METHODS: This was a Phase IIa, multicenter, parallel-group, double-blind, three-arm, placebo-controlled, four-week, randomized study with two doses of GSK256066 (25 mug, 87.5 mug). The primary endpoint was safety and tolerability. Secondary endpoints included changes in inflammatory markers in induced sputum and blood, lung function (spirometry, body plethysmography, impulse oscillometry), and pharmacokinetics. RESULTS: 104 patients were randomized and 94 patients completed the study. The incidence and intensity of treatment-related adverse events were similar between treatment groups. The most frequent adverse event was nasopharyngitis and there were no serious adverse events in patients receiving GSK256066. The overall incidence of gastrointestinal adverse events was low in all treatment groups. There were no statistically significant changes in inflammatory markers in induced sputum and blood following treatment with GSK256066. Analysis of sputum mRNA suggested engagement of pharmacology, based on increased expression of cAMP-dependent genes including amphiregulin and CREM in subjects receiving GSK256066. There was a trend for an increase in post-bronchodilator FEV1 for both doses of GSK256066; in addition, for the 87.5 mug group, there was a mean reduction in residual volume of 0.367 L (95% confidence interval: 0.112, 0.622 L) relative to placebo. CONCLUSIONS: Administration of inhaled GSK256066 was well-tolerated in patients with moderate COPD. Further studies would be required to confirm the favorable safety profile and to demonstrate clinical efficacy of this compound. (ClinicalTrials.gov identifier: NCT00549679).

The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma.[Pubmed:20193079]

Respir Res. 2010 Mar 1;11:26.

UNLABELLED: GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics. METHODS: In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR. RESULTS: GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects. CONCLUSIONS: GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma.

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.

GSK256066,801312-28-7,Natural Products,PDE, buy GSK256066 , GSK256066 supplier , purchase GSK256066 , GSK256066 cost , GSK256066 manufacturer , order GSK256066 , high purity GSK256066