GSK256066, an Exceptionally High-Affinity and Selective Inhibitor of Phosphodiesterase 4 Suitable for Administration by Inhalation: In Vitro, Kinetic, and In Vivo Characterization

Abstract

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-, 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 Ͻ0.5 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 ␣ 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 (Ͼ380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and Ͼ2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (Ͼ17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED 50 values of 1.1 g/kg (aqueous suspension) and 2.9 g/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED 50 9.3 g/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.

CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration

“…The rank order of potency of the compounds (confidence interval values given in parentheses) is the following: GSK256066, IC 50 5 3 pM (2-4), CHF6001, IC 50 5 28 pM (21-40), roflumilast IC 50 5 1.77 nM (0.45-6.83), UK-500,001, IC 50 5 12.1 nM (2.9-50.1), and cilomilast IC 50 5 165.3 nM (61.8-442.6). These results were well in agreement with the previously reported potencies of GSK256066, roflumilast, and cilomilast against TNF-a release in PBMCs (Hatzelmann and Schudt, 2001;Tralau-Stewart et al, 2011). In human THP-1 monocytic-derived macrophages, basal release of TNF-a (mean 6 S.D.)…”

“…Lack of efficacy in phase 2 trials in asthma and COPD led to the discontinuation also of AWD 12-281 [N-(3,5-dichloropyridin-4-yl)-2-(1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl)-2-oxoacetamide] and tofimilast (Pagès et al, 2009). To date, the best in class among inhaled PDE4 inhibitors is GSK256066, which appears to be more potent than all the other PDE4 inhibitors described so far Tralau-Stewart et al, 2011), is well tolerated in COPD patients (Watz et al, 2013), and is effective in reducing allergen challenge responses in asthma patients (Singh et al, 2010).…”

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

“…Recently, more and more novel selective PDE4 inhibitors (as shown in Table 2) have been designed and explored in diferent rodent models, displaying a safer proile compared to traditional agents [107][108][109][110][111]; [66,75], supporting further evaluation of these novel PDE4 inhibitors in a clinical seting.…”

In Vivo Characterization of GSK256066, a High-Affinity Inhaled Phosphodiesterase 4 Inhibitor

“…The preliminary pharmacology of GSK256066 has been described (Knowles et al, 2009b;Tralau-Stewart et al, 2010). GSK256066 is more potent than all of the other PDE4 inhibitors described to date, e.g., approximately 10,000-fold more potent in the PDE4B enzyme assay than roflumilast (pIC 50 Ն 11.5 versus 9.6) and is highly selective over other PDEs (Ͼ1400-fold versus PDE7 and Ͼ350,000 versus PDE1, PDE2, PDE3, PDE5, and PDE6).…”