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Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies

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Book cover Phosphodiesterases as Drug Targets

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 204))

Abstract

Phosphodiesterase (PDE) 4 inhibitors have been in development as a novel anti-inflammatory therapy for more than 20 years, with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, only one selective PDE4 inhibitor, roflumilast (Daxas ®), has been approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD. In many other cases, the development of PDE4 inhibitors of various structural classes has been discontinued due to lack of efficacy and/or dose-limiting adverse events. Indeed, for many of these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose–response curve. Thus, a significant ongoing challenge that faces the pharmaceutical industry is to synthesize compounds with therapeutic ratios that are superior to roflumilast. Several strategies are being considered, but clinically effective compounds with an optimal pharmacophore have not, thus far, been reported. In this chapter, alternative means of harnessing the clinical efficacy of PDE4 inhibitors are described. These concepts are based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as a glucocorticoid.

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Abbreviations

AHR:

Airway hyperresponsiveness

AP:

Activator protein

AR:

Androgen receptor

BP:

Blood pressure

CNS:

Central nervous system

COPD:

Chronic obstructive pulmonary disease

FEV1 :

Forced expiratory volume in 1 s

GILZ:

Glucocorticoid-induced leucine zipper

GR:

Glucocorticoid receptor

GRE:

Glucocorticoid response element

HDAC:

Histone deacetylase

HPV:

Hypoxic pulmonary vasoconstriction

HR:

Heart rate

ICS:

Inhaled corticosteroid

IL:

Interleukin

LABA:

Long-acting β2-adrenoceptor agonist

LVP:

Left ventricular pressure

MKP:

Mitogen-activated protein kinase phosphatase

MR:

Mineralocorticoid receptor

NFκB:

Nuclear factor-kappaB

PDE:

Phosphodiesterase

PH:

Pulmonary hypertension

PHA:

Phytohemagglutinin

PKA:

cAMP-dependent protein kinase

Ppa:

Pulmonary artery pressure

PR:

Progesterone receptor

PVR:

Pulmonary vascular resistance

RAR/RXR:

Retinoic acid receptors

SABA:

Short-acting β2-adrenoceptor agonist

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Acknowledgments

RN is a Canadian Institutes of Health Research (CIHR) New Investigator and an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar. Work in the laboratories of RN and MAG is supported by CIHR operating grants (MOP 68828 and MOP 93742, respectively) and educational research grants from AstraZeneca, Gilead Sciences, GlaxoSmithKline, and Nycomed.

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Authors and Affiliations

  1. Airways Inflammation Research Group, Departments of Physiology and Pharmacology, Institute of Infection, Immunity and Inflammation, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada

    Mark A. Giembycz

  2. Cell Biology and Anatomy, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, AB, Canada

    Robert Newton

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  1. Mark A. Giembycz
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  2. Robert Newton
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Correspondence to Mark A. Giembycz .

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  1. School of Medicine, Dept. Molecular Physiology & Biophysics, Vanderbilt University, Light Hall 702, Nashville, 37232-0615, Tennessee, USA

    Sharron H. Francis

  2. HSW 1656, Center for Reproductive Sciences, Parnassus Avenue 513, San Francisco, 94143-0556, California, USA

    Marco Conti

  3. Wolfson Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom

    Miles D. Houslay

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Giembycz, M.A., Newton, R. (2011). Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_18

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