Differential Effects of PDE4 Inhibitors on Cortical Neurons and T-Lymphocytes

Hirose, Ryo; Manabe, Haruhiko; Yanagawa, Koji; Ohshima, Etsuo; Ichimura, Michio

doi:10.1254/jphs.fp0071463

Cited by 8 publications

(7 citation statements)

References 32 publications

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“…The data presented demonstrate that GSK256066 is an exceptionally high-affinity inhibitor of PDE4B, substantially more so than the other known PDE4 inhibitors tested (Table 2), including the most potent of the oral inhibitors roflumilast (Hatzelmann and Schudt, 2001) and the inhaled inhibitors AWD 12-281 (Kuss et al, 2003), tofimilast (Duplantier et al, 2007), and piclamilast (Hirose et al, 2008). GSK256066 is highly selective for PDE4 over other PDEs tested (Ͼ2500-fold against PDE7 and Ͼ380,000 against PDE1, PDE2, PDE3, PDE5, and PDE6) and also has a high HARBS/PDE4B ratio (Ͼ17).…”

Section: Discussionmentioning

confidence: 81%

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

Tralau-Stewart¹,

Williamson²,

Nials³

et al. 2011

J Pharmacol Exp Ther

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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.

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Section: Discussionmentioning

confidence: 81%

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

Tralau-Stewart¹,

Williamson²,

Nials³

et al. 2011

J Pharmacol Exp Ther

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“…On the day of treatment, the attached HT-22 cells were washed with warm phosphate buffer saline (PBS) and then incubated for 10 min with PBS supplemented with various concentrations of A-33 or D159687 and further for 10 min with 10 nM isoproterenol in the system52. After incubation, PBS containing the drugs was removed and the plates were let dry roughly before 200 μl HCl (0.1 M) was added to each well to lyse the cells.…”

Section: Methodsmentioning

confidence: 99%

Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

Zhang

et al. 2017

Sci Rep

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Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions.

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“…The first generation of PDE4‐selective inhibitors improved selectivity over theophylline; one of these was the prototypical drug rolipram 42 . Rolipram has been investigated for lung diseases, but its use has been limited by side effects, including nausea and vomiting 2 , 43 . Upon further investigation, it was determined that PDE4s exist in two conformations: a high‐affinity rolipram‐binding conformation and a low‐affinity rolipram‐binding conformation 44 .…”

Section: Generations Of Pde4 Inhibitorsmentioning

confidence: 99%

“…42 Rolipram has been investigated for lung diseases, but its use has been limited by side effects, including nausea and vomiting. 2,43 Upon further investigation, it was determined that PDE4s exist in two conformations: a high-affinity rolipram-binding conformation and a low-affinity roliprambinding conformation. 44 The adverse side effects of rolipram and related compounds were determined to occur when rolipram inhibited high-affinity rolipram-binding-conformation PDE4s, although the specific biological sequelae of these conformations are still not fully understood.…”

Section: Generations Of Pde4 Inhibitorsmentioning

confidence: 99%

PDE4: A Novel Target in the Treatment of Chronic Obstructive Pulmonary Disease

Michalski

Golden

Ikari

et al. 2011

Clin Pharmacol Ther

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Phosphodiesterases (PDEs) are important modulators of inflammation and wound healing. In this capacity, specific targeting of PDEs for the treatment of many diseases, including chronic obstructive pulmonary disease (COPD), has been investigated. Currently, treatment of COPD is suboptimal. PDE4 modulates the inflammatory response of the lung, and inhibition of PDE4 may be a novel, COPD‐specific approach toward more effective treatment strategies. This review describes the state of PDE4‐inhibitor therapy for use in COPD treatment. Clinical Pharmacology & Therapeutics (2012); 91 1, 134–142. doi:

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Differential Effects of PDE4 Inhibitors on Cortical Neurons and T-Lymphocytes

Cited by 8 publications

References 32 publications

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

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

Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

PDE4: A Novel Target in the Treatment of Chronic Obstructive Pulmonary Disease

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