Limits...
Potential mechanisms to explain how LABAs and PDE4 inhibitors enhance the clinical efficacy of glucocorticoids in inflammatory lung diseases.

Giembycz MA, Newton R - F1000Prime Rep (2015)

Bottom Line: This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose.In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy.Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary 3820 Hospital Drive NW, Calgary, Alberta Canada T2N 1N4.

ABSTRACT
Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid. This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and another class of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy of inhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled glucocorticoid/LABA combination therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

No MeSH data available.


Related in: MedlinePlus

Structure of the heterobifunctional ligand GS-5759Bifunctional ligands contain two pharmacophores that are joined covalently by an appropriately designed “spacer” at, so-called, linker sites (cartoon). GS-5759 is composed of the quinolin-2-one present in the long-acting β2-adrenoceptor agonists (LABAs) indacaterol and carmoterol (pink), and the phosphodiesterase 4 (PDE4) inhibitor GlaxoSmithKline (GSK) 256066 (blue) that have been linked covalently by a pent-1-yn-1-yl benzene spacer (black). The asterisk indicates chiral centre. Adapted from [97].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4335793&req=5

fig-003: Structure of the heterobifunctional ligand GS-5759Bifunctional ligands contain two pharmacophores that are joined covalently by an appropriately designed “spacer” at, so-called, linker sites (cartoon). GS-5759 is composed of the quinolin-2-one present in the long-acting β2-adrenoceptor agonists (LABAs) indacaterol and carmoterol (pink), and the phosphodiesterase 4 (PDE4) inhibitor GlaxoSmithKline (GSK) 256066 (blue) that have been linked covalently by a pent-1-yn-1-yl benzene spacer (black). The asterisk indicates chiral centre. Adapted from [97].

Mentions: In contrast, bifunctional ligands are single chemical entities that contain two pharmacophores joined covalently by an optimally designed “spacer” at, so-called, linker sites (Figure 2) [97,98,99]. Typically, such ligands have a high molecular weight. For an inhaled drug, this often translates into greater lung retention, low oral bioavailability and reduced systemic exposure [98]. Moreover, the clinical development of bifunctional ligands is simplified in terms of matched pharmacokinetics, formulation and, critically, identical deposition characteristics [99]. GS-5759 is a novel, heterobifunctional ligand developed by Gilead Sciences [100] for COPD in which the exceptionally potent PDE4 inhibitor, GlaxoSmithKline (GSK) 256066 [101], is conjugated to the active head group of the LABAs, indacaterol and carmoterol, via a pent-1-yn-1yl benzene spacer (Figure 3) [100,102,103]. This molecule has a similar potency at both targets and has been optimised for inhaled delivery with potential as a first-line therapy in COPD or combined with an inhaled glucocorticoid as part of a triple combination therapy within a single inhaler device. Clearly, the cAMP signal generated by concurrent PDE4 inhibition and β2-adrenoceptor activation produced by a single molecule in the same cell over a similar concentration range would allow a greater therapeutic benefit of a glucocorticoid to be realised, especially in target tissues in which β2-adrenoceptor number is limiting.


Potential mechanisms to explain how LABAs and PDE4 inhibitors enhance the clinical efficacy of glucocorticoids in inflammatory lung diseases.

Giembycz MA, Newton R - F1000Prime Rep (2015)

Structure of the heterobifunctional ligand GS-5759Bifunctional ligands contain two pharmacophores that are joined covalently by an appropriately designed “spacer” at, so-called, linker sites (cartoon). GS-5759 is composed of the quinolin-2-one present in the long-acting β2-adrenoceptor agonists (LABAs) indacaterol and carmoterol (pink), and the phosphodiesterase 4 (PDE4) inhibitor GlaxoSmithKline (GSK) 256066 (blue) that have been linked covalently by a pent-1-yn-1-yl benzene spacer (black). The asterisk indicates chiral centre. Adapted from [97].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4335793&req=5

fig-003: Structure of the heterobifunctional ligand GS-5759Bifunctional ligands contain two pharmacophores that are joined covalently by an appropriately designed “spacer” at, so-called, linker sites (cartoon). GS-5759 is composed of the quinolin-2-one present in the long-acting β2-adrenoceptor agonists (LABAs) indacaterol and carmoterol (pink), and the phosphodiesterase 4 (PDE4) inhibitor GlaxoSmithKline (GSK) 256066 (blue) that have been linked covalently by a pent-1-yn-1-yl benzene spacer (black). The asterisk indicates chiral centre. Adapted from [97].
Mentions: In contrast, bifunctional ligands are single chemical entities that contain two pharmacophores joined covalently by an optimally designed “spacer” at, so-called, linker sites (Figure 2) [97,98,99]. Typically, such ligands have a high molecular weight. For an inhaled drug, this often translates into greater lung retention, low oral bioavailability and reduced systemic exposure [98]. Moreover, the clinical development of bifunctional ligands is simplified in terms of matched pharmacokinetics, formulation and, critically, identical deposition characteristics [99]. GS-5759 is a novel, heterobifunctional ligand developed by Gilead Sciences [100] for COPD in which the exceptionally potent PDE4 inhibitor, GlaxoSmithKline (GSK) 256066 [101], is conjugated to the active head group of the LABAs, indacaterol and carmoterol, via a pent-1-yn-1yl benzene spacer (Figure 3) [100,102,103]. This molecule has a similar potency at both targets and has been optimised for inhaled delivery with potential as a first-line therapy in COPD or combined with an inhaled glucocorticoid as part of a triple combination therapy within a single inhaler device. Clearly, the cAMP signal generated by concurrent PDE4 inhibition and β2-adrenoceptor activation produced by a single molecule in the same cell over a similar concentration range would allow a greater therapeutic benefit of a glucocorticoid to be realised, especially in target tissues in which β2-adrenoceptor number is limiting.

Bottom Line: This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose.In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy.Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary 3820 Hospital Drive NW, Calgary, Alberta Canada T2N 1N4.

ABSTRACT
Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid. This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and another class of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy of inhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled glucocorticoid/LABA combination therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

No MeSH data available.


Related in: MedlinePlus