The therapeutic potential of PDE4 inhibitors

Abstract

Phosphodiesterase enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 inhibitors have been well documented both in vitro and in vivo in a variety of animal models. The potential use of PDE4 inhibitors as anti-inflammatory agents for the treatment of asthma and other inflammatory disorders has received considerable attention from the pharmaceutical industry, but to date, there are no selective PDE4 inhibitors on the market. Early PDE4 inhibitors, typified by rolipram, suffered from dose-limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second generation compounds, including CDP840 and SB207499 (Ariflo), have been identified with reduced side effect liability. Recent evidence suggests a correlation between side effects and the ability of compounds to bind at the so-called high affinity rolipram binding site (HPDE), whilst beneficial effects appear to correlate with binding at the catalytic site. A number of companies are actively pursuing compounds which exhibit improved affinity for the catalytic site and reduced affinity for the HPDE, in the expectation that this will provide compounds with an improved therapeutic index.

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

“…Despite these data, the potential use of rolipram for depression was limited because of side effects such as nausea and emesis. Second-generation compounds with markedly improved tolerability are being developed (Dyke and Montana, 2002;Huang et al, 2001), and it is anticipated that the availability of CNS-penetrant PDE4 inhibitors may lead to the development of a novel class of antidepressants.…”

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

“…Recent studies demonstrating that PDE4 is expressed in inflammatory cells, such as eosinophils, and that inhibition of PDE4 down-regulates the inflammatory response have generated renewed excitement about the possible utility of this class of agents in the treatment of diseases such as asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, Crohn's disease, and multiple sclerosis (Dyke and Montana 2002;Huang et al 2001). Secondgeneration compounds with markedly improved tolerability are rapidly being developed (Dyke and Montana 2002;Huang et al 2001), and it is anticipated that the availability of CNS-penetrant PDE4 inhibitors may lead to the development of a novel class of antidepressants.…”

“…Secondgeneration compounds with markedly improved tolerability are rapidly being developed (Dyke and Montana 2002;Huang et al 2001), and it is anticipated that the availability of CNS-penetrant PDE4 inhibitors may lead to the development of a novel class of antidepressants.…”

Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases

“…Even so, chemical inhibitors of PDEs, and in some cases chemical activators, are seen as potential therapeutic compounds for the treatment of a variety of conditions including neurological diseases such as anxiety, depression, and Alzheimer's disease; inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension; metabolic diseases such as diabetes and obesity; and other conditions such as memory loss, chronic lymphocytic leukemia, prostate cancer, and erectile dysfunction. [2][3][4][5][6][7][8][9] We describe here the development of a cell-based screen for identifying both chemical inhibitors and activators of cAMP PDEs using a simple growth assay in the fission yeast…”