Phosphodiesterase 4 Inhibitors for the Treatment of COPD

doi:10.1378/chest.121.5_suppl.192S

Chest

Volume 121, Issue 5, Supplement, May 2002, Pages 192S-196S

https://doi.org/10.1378/chest.121.5_suppl.192S Get rights and content

Phosphodiesterase 4 (PDE4) is a major cyclic adenosine-3′,5′-monophosphate-metabolizing enzyme in immune and inflammatory cells, airway smooth muscle, and pulmonary nerves. Selective inhibitors of this enzyme have been available for a number of years and show a broad spectrum of activity in animal models of COPD and asthma. The class-associated side effects, mainly nausea and emesis, appear to have been at least partially overcome by the so-called “second-generation” PDE4 inhibitors. Currently, three companies are in the later stages of development of candidate second-generation PDE4 inhibitors for the treatment of COPD patients. The preclinical profile of one of these, BAY 19–8004, is summarized below. The initial clinical data on the most advanced compound, cilomilast, were indeed encouraging. However, full knowledge of the therapeutic value of this novel compound class awaits the outcome of longer term clinical trials.

Section snippets

In Vitro

BAY 19–8004 is representative of a new structural class of PDE4 inhibitors, the benzofurans. The profile of BAY 19–8004 in vitro is summarized in Table 1. In common with cilomilast and roflumilast, it is highly selective for PDE4. The mean concentration required for 50% inhibition of PDE4 that was present in a membrane preparation from human neutrophils was 67 nm. As an inhibitor of other PDE1, -2, -3, and -5 isoform enzymes from a variety of sources, BAY 19–8004 showed < 50% inhibition at a

Class-Associated Side Effects

The promise that PDE4 inhibitors will have an improved side-effect profile over nonselective compounds has been borne out in early clinical trials, at least with regard to cardiovascular and most CNS side effects. However, GI side effects, including nausea, vomiting, and dyspepsia, limit the dosages of these compounds that can be administered to humans.^16,^17,¹⁸

The long splice variants of PDE4 can exist as two conformers. One with a high affinity for rolipram predominates in parietal cells and

Summary of Phase 1 Findings With BAY 19–8004

BAY 19–8004 exhibited linear pharmacokinetics with a half-life of 25 h and low plasma clearance in phase 1 studies. There was low intersubject variability. A once-daily administration of 5 mg (the highest dose subsequently used in phase II COPD studies) to elderly patients achieved plasma levels in the range associated with efficacy in animal models (maximum plasma concentration, 68 ng/mL; minimum plasma concentration, 40 ng/mL at steady state). Once-daily administration is therefore the dosing

What Will Third-Generation PDE4 Inhibitors Look Like?

From the available information on cilomilast, it appears that while the side effects are apparently tolerated at a dose showing efficacy (ie, 15 mg bid), they are still a significant problem and almost certainly limit the dose.

Two strategies for further improvement in the therapeutic window of PDE4 inhibitors can be envisaged. The finding that PDE4 exists as four genetically distinct subtypes offers the possibility of identifying subtype-selective inhibitors. There is some evidence that such

Conclusion

The preclinical data supporting the potential utility of PDE4 inhibitors in COPD are compelling. The observed efficacy of cilomilast in COPD patients also is encouraging. However, it is not clear whether the visible effects on lung function and symptom score are a manifestation of the bronchodilator activity of PDE4 inhibitors or are a consequence of anti-inflammatory effects. Early reports suggest that significant anti-inflammatory effects were not seen. The optimal positioning of PDE4

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Development and optimization of RofA-PAMAM dendrimer complex materials for sustained drug delivery
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Subsequently, manage other symptoms of the disease by comprehending oral corticosteroids like budesonide, formoterol [6], bronchodilators [7], long-acting beta-agonists, 5-lipoxygenase inhibitor, long-term home oxygen therapy, anticholinergic agents like ipratropium, tiotropium, methylxanthines like theophylline [8–13], and inhaled corticosteroids (ICS) [14] like fluticasone propionate [15,16], and theophylline combined with bronchodilators and corticosteroids [17]. Nevertheless, a superfamily of eleven enzymes of phosphodiesterase (PDE) discovered in 1958 was observed [18] restraining the metabolism of cyclic nucleotides [19] and as signaling molecules in a variety of cells. The inhibition of which potentially improved the inflammatory outline [20].
The current indagation is observed on anatomization of drug release dynamics aiming at preceding the anti-inflammation activity of roflumilast analogue (RofA), post assemblage with dendrimer. The study pondered the development and optimization of RofA-Dendrimer complexes for sustained delivery. Various physicochemical characteristics, like encapsulation potency, drug loading, drug release, dissolvability, stability, and anti-inflammation activity were determined. The study results in the observation of encapsulation potency of 72.64 ± 0.189 %, loading capability of 63.41 ± 0.166 %, and in vitro release of RofA-4.0 G PAMAM complex was found to increase making it an appropriate candidate for sustained drug release ~~progressively~~. It has been found by constructing drug release kinetics, that the release followed was a non- fickian diffusion ( n < 0.89). The phase solubility diagram indicated an increment of solubility of RofA with varied dendrimer generation as well as pH. The study was initiated to prepare a suited candidate fit to scale back site-specific inflammation. Further concluding the contemplation for its sustained delivery, enhanced solubility, and potentially augmented anti-inflammation activity.
V̇/Q̇ Mismatch: A Novel Target for COPD Treatment
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In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation ( $\dot{V}$ A), capillary perfusion ( $\dot{Q}$ c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low $\dot{V}$ A/ $\dot{Q}$ c, or wasted ventilation related to high $\dot{V}$ A/ $\dot{Q}$ c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on $\dot{V}$ A (bronchodilators, antiinflammatory medications) or $\dot{Q}$ c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with $\dot{V}$ A/ $\dot{Q}$ c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity.
Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile
2018, European Journal of Medicinal Chemistry
Citation Excerpt :
Many treatments had been developed for COPD as inhaled corticosteroids [6–9], inhibitors of inducible nitric oxide synthase (i-NOS) [10], leukotriene inhibitors [11,12], adhesion-molecule blockers [13], chemokine inhibitors [14], TNFα inhibitors [15], NFκB inhibitors [16], p38 MAPK inhibitors [17], Phosphoinositide 3-kinase (PI3K) inhibitors [18] and Peroxisome proliferator-activated receptors (PPARs) activators [19–21]. The discovery of selective phosphodiesterase 4 (PDE-4) inhibitors as a way for treatment of inflammation in COPD patients was prompted when it has been observed that raising the intracellular levels of 3′5′-cyclic adenosine monophosphate (cAMP) can inhibit the functions of inflammatory cells and also due to the wide distribution of PDE-4 enzymes in inflammatory cells and in the lung [22–24], There are 11 distinct enzymes of PDEs [25,26] in which PDE-4 specifically inactivates cAMP which is highly expressed in inflammatory cells, and so, inhibitors of PDE-4 enzyme cause a decrease in inflammatory response which is increased in COPD [27,28], PDE-4 enzymes are classified into 4 subtypes (4A-D) which show a similarity of 78% in the active catalytic site [29]. It has been revealed that selective inhibition of PDE-4B showed a potent anti-inflammatory effect not associated with emesis side effect accompanied with the inhibition of PDE-4D enzyme [30–32].
In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CL_int (5.67 mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21 h) and a C_max value of 113.958 ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD.
Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors
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Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure–activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-α production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis.
MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers
2008, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Inhibition of PDE-4 increases the intra-cellular levels of cyclic adenosine monophosphate (cAMP) followed by increased protein kinase A (PKA) activation. Active PKA suppresses the activity of inflammatory cells and causes direct airway smooth muscle relaxation [9,11]. Furthermore, specific PDE-4 inhibition does not interfere with the adenosine receptor, the cause of arrhythmias and seizures [4].
MK-0873 is a novel selective phosphodiesterase-4 inhibitor, which has been in development for the treatment of chronic obstructive pulmonary disease (COPD). In this indication, theophylline is still an important treatment, despite its relatively small therapeutic window. In view of this, it is important to investigate whether MK-0873 could affect the pharmacokinetics, safety and tolerability of theophylline, when both drugs are given concomitantly.
The objective of this study was to investigate the effect of multiple doses of oral MK-0873, a selective phosphodiesterase-4 inhibitor, on the pharmacokinetics, safety and tolerability profile of orally administered theophylline in healthy volunteers.
Eight healthy, non-smoking male subjects participated in this randomized, open-label, 2-period, cross-over study. In one period subjects received an oral dose of 2.5 mg MK-0873 for 6 days co-administered with a single oral dose of 250 mg theophylline on day 5. The other period consisted of a single dose of 250 mg theophylline on day 1. In each period, blood samples were collected at predefined time points to evaluate theophylline pharmacokinetics.
All subjects completed the study. The study medications were generally well tolerated and no clinically relevant changes were observed in either treatment periods. No significant difference was found in the AUC 0–∞ (77.7 vs. 83.8 h ng/ml; p=0.280) and C_max (6.70 vs. 7.77 ng/ml; p=0.125) of theophylline between the MK-0873+theophylline and theophylline only treatment, and bioequivalence was demonstrated for AUC0–∞ (geometric mean ratio with 90% confidence interval: 0.930 (0.826, 1.047)).
In this study, in a limited number of subjects, co-administration of oral MK-0873 did not affect the pharmacokinetics, safety, and tolerability of oral theophylline in non-smoking healthy male subjects.

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Chest

Phosphodiesterase 4 Inhibitors for the Treatment of COPD

Section snippets

In Vitro

Class-Associated Side Effects

Summary of Phase 1 Findings With BAY 19–8004

What Will Third-Generation PDE4 Inhibitors Look Like?

Conclusion

Lancet

Trends Pharmacol Sci

Eur J Pharmacol

Structural and inflammatory changes in COPD: a comparison with asthma

Thorax

PEUROSCOP, ISOLDE and the Copenhagen city lung study

Thorax

Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease

N Engl J Med

Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD

Am J Respir Crit Care Med

Effect of fluticasone propionate on induced sputum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with COPD

Am J Respir Crit Care Med

Phosphodiesterase isozymes: molecular targets for novel antiasthma agents

Am J Respir Crit Care Med

Prostagladin E2 inhibits apoptosis in human neutrophilic polymorphonuclear leukocytes: role of intracellular cyclic AMP levels

Exp Hematol

Ariflo (SB 207499), a second generation oral PDE4 inhibitor, improves quality of life in patients with COPD [abstract]

Am J Respir Crit Care Med