Inhaled Phosphodiesterase 4 (PDE4) Inhibitors for Inflammatory Respiratory Diseases

Phillips, Jonathan E.

doi:10.3389/fphar.2020.00259

Cited by 85 publications

(85 citation statements)

References 51 publications

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“…In particular, cAMP-specific PDE4 type is widely present in immune cells including neutrophils and contributes to neutrophil-mediated lung inflammation ( Baillie et al, 2019 ). There are currently three FDA-approved PDE4 inhibitors: roflumilast for COPD ( Phillips, 2020 ), apremilast for psoriasis ( Queiro Silva et al, 2020 ), and crisaborole for atopic dermatitis ( Hashim et al, 2020 ). Other drugs such as CHF6001 (NCT02986321 for COPD and NCT01689571 for asthma) ( Singh et al, 2019 ), and ensifentrine (RPL554, NCT04027439 for COPD) ( Cazzola et al, 2019 ) are awaiting phase 3 clinical trials.…”

Section: Drugs Targeting Neutrophils For Covid-19 Associated Ardsmentioning

confidence: 99%

“…Other drugs such as CHF6001 (NCT02986321 for COPD and NCT01689571 for asthma) ( Singh et al, 2019 ), and ensifentrine (RPL554, NCT04027439 for COPD) ( Cazzola et al, 2019 ) are awaiting phase 3 clinical trials. However, many of the experimental drugs were discontinued in clinical trials due to side effects ( Phillips, 2020 ). Several PDE inhibitors have been proposed to be suitable drugs for COVID-19 treatment ( Giorgi et al, 2020 ).…”

Section: Drugs Targeting Neutrophils For Covid-19 Associated Ardsmentioning

confidence: 99%

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Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

et al. 2020

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This review describes targeting neutrophils as a potential therapeutic strategy for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19), a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutrophil counts are significantly elevated in patients with COVID-19 and significantly correlated with disease severity. The neutrophil-to-lymphocyte ratio can serve as a clinical marker for predicting fatal complications related to ARDS in patients with COVID-19. Neutrophil-associated inflammation plays a critical pathogenic role in ARDS. The effector functions of neutrophils, acting as respiratory burst oxidants, granule proteases, and neutrophil extracellular traps, are linked to the pathogenesis of ARDS. Hence, neutrophils can not only be used as pathogenic markers but also as candidate drug targets for COVID-19 associated ARDS.

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Section: Drugs Targeting Neutrophils For Covid-19 Associated Ardsmentioning

confidence: 99%

Section: Drugs Targeting Neutrophils For Covid-19 Associated Ardsmentioning

confidence: 99%

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

et al. 2020

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“…[35][36][37] Briey, the general methods for the synthesis of compounds Iad are discussed below. Previous reports suggested the E conguration of compounds Ia-d. 26 Furthermore, both Z and E conformers energies were minimized and the calculated total energy of compound Ic was 117.266 kcal mol À1 , which is lower if it is in E conguration ( Table 1). 2.1.1.…”

Section: Chemistrymentioning

confidence: 99%

Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins

2020

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“…The aim of this approach is not only to achieve a more precise blockade of these enzymes but also to reduce the side effects of non-selective PDE inhibitors. Several inhibitors have undergone clinical trials, and some of them, such as roflumilast (a PDE4 inhibitor), are currently used in the clinic [12]. Another example is the inhaled PDE4 inhibitor, CHF6001 currently in phase II clinical trials, which also exhibits preferential anti-inflammatory properties in COPD [13].…”

Section: Introductionmentioning

confidence: 99%

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

Wójcik-Pszczoła

Chłoń-Rzepa

Jankowska

et al. 2020

IJMS

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Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832—a pan-PDE inhibitor, 869—a TRPA1 modulator, and 145—a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.

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Inhaled Phosphodiesterase 4 (PDE4) Inhibitors for Inflammatory Respiratory Diseases

Cited by 85 publications

References 51 publications

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

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