Review
doi: 10.1038/bjp.2008.307. Epub 2008 Jul 28.PDE4 inhibitors: current status
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- PMID:18660825
- PMCID: PMC2567892
- DOI: 10.1038/bjp.2008.307
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Review
PDE4 inhibitors: current status
D Spina. Br J Pharmacol.2008 Oct.
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Abstract
Phosphodiesterase4 inhibitors are currently under development for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease. The rationale for the development of this drug class stems from our understanding of the role of PDE4 in suppressing the function of a range of inflammatory and resident cells thought to contribute toward the pathogenesis of these diseases. Similarly, numerous preclinical in vivo studies have shown that PDE4 inhibitors suppress characteristic features of these diseases, namely, cell recruitment, activation of inflammatory cells and physiological changes in lung function in response to a range of insults to the airways. These potentially beneficial actions of PDE4 inhibitors have been successfully translated in phase II and III clinical trials with roflumilast and cilomilast. However, dose limiting side effects of nausea, diarrhoea and headache have tempered the enthusiasm of this drug class for the treatment of these respiratory diseases. A number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects, including delivery via the inhaled route, and/or development of non-emetic PDE4 inhibitors and mixed PDE inhibitors.
Figures
Line graph drawn from data presented in Table 2 of Robichaudet al. (1999) showing the number of retches (a) and the percentage of animals who retch (b) in response to increasing p.o doses of PDE4 inhibitors, PMNPQ (open circles), R-rolipram (closed circles) and CT-2450.1Inhibitory potency (IC50) for these inhibitors against human cloned PDE4 subtypes.2Concentration of PDE4 inhibitors measured in homogenates of whole brain and in plasma 1 h following systemic administration of drug.3IC50 values against whole blood tumour necrosis factor-α (references cited in Robichaudet al. 2002b). CT-2450, (R)-N-(4-[1-3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl)-N′-ethylurea; PMNPQ; 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline.
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