New Avenues for Phosphodiesterase Inhibitors in Asthma

Abstract

Introduction: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease. Areas Covered: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma. Expert Opinion: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.

Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation

“…In the recent years, many attempts have been made to search for anti-fibrotic drugs, both in the group of already known and used substances, as well as in entirely new groups of chemical compounds [34][35][36][37]. Lately, there has been a growing interest in selective or dual PDE inhibitors, especially active against the PDE3, PDE4, PDE5, or PDE7 and PDE8 isoforms, as therapeutic targets for respiratory diseases [14,18]. Some of them, e.g., roflumilast, sildenafil, or tadalafil, have already been used in the clinic, and others, which are mainly inhaled PDE4 and/or PDE3 inhibitors, are intensively evaluated in numerous clinical trials [16].…”

“…Lately, a large body of evidence points to phosphodiesterase (PDE) inhibitors as promising anti-inflammatory and anti-fibrotic agents [14][15][16][17][18]. Phosphodiesterases are cellular enzymes responsible for the breakdown of the secondary signaling transducersadenosine 3 ,5 -cyclic monophosphate (cAMP) and guanosine 3 ,5 -cyclic monophosphate (cGMP).…”

The future of inhalation therapy in chronic obstructive pulmonary disease

“…At present, only roflumilast has been approved for clinical use and, in any case, it is burdened by side effects that considerably reduce patient compliance ( Cazzola et al., 2016 ). The inhalation route could be used to reduce the detrimental effects of PDE4 inhibitors ( Matera et al., 2014 , 2021d ). However, the development of almost all inhaled PDE4 inhibitors was discontinued because they produced only modest clinical benefits in patients with COPD.…”

“…As knowledge about the pathogenesis and evolution of COPD has expanded, it has become increasingly obvious that the treatment of COPD cannot be limited to the use of classical inhaled bronchodilators (β 2 agonists and muscarinic antagonists) and corticosteroids ( Cazzola and Matera, 2021 ). Some new drugs are in development ( Cazzola et al., 2019a ; Rogliani et al., 2020 ; Matera et al., 2021a , 2021b , 2021c ; Ora et al., 2020a ), but it is difficult to predict which ones will be approved for clinical use because the translation to humans of interventions that are effective in animal models is always not easy and often unreliable ( Cazzola and Matera, 2021 ).…”

Can Phosphodiesterase 4 Inhibitor Therapy Be Used in Respiratory Diseases Other Than Chronic Obstructive Pulmonary Disease?

“…The epidemiological data on uncontrolled asthma and the economic burden per each asthma patient per year, which has been calculated as USD 1,000, highlight the necessity of novel therapeutic options in asthma management [ 22 ]. Even though researchers and clinicians repeatedly expressed the possibility of using PDE inhibitors in asthma therapy due to their effective bronchodilator and anti-inflammatory properties, none of the PDE4 inhibitors has entered the market as asthma therapy in the past three decades [ 17 ].…”