An increase of cyclic
adenosine and
guanosine monophosphate (cAMP and cGMP) level can be achieved by inhibition of
phosphodiesterases (
PDEs), which are the
enzymes responsible for the conversion of these second messengers into the corresponding 5-monophosphate inactive counterparts. The high heterogeneity in PDE families and in their tissue distribution, as well as their different functional role, make these
enzymes very attractive targets for medicinal chemists. The PDE 4 family is particularly abundant in immunocompetent cells, where an increase of cAMP leads to the inhibition of the synthesis and release of pro-inflammatory mediators,
cytokines and
active oxygen species. Moreover
PDE 4 inhibitors are able to reduce bronchial smooth muscle tone in vitro and show bronchodilatory effects in vivo. Thus, the current
therapy for
asthma, which is based on a combination of beta(2) agonists and
corticosteroids, could be replaced by treatment with
PDE 4 inhibitors. This review mainly covers
PDE 4 inhibitors structurally related to
xanthines and
Nitraquazone, which appear to be very attractive models for the synthesis of novel
PDE 4 inhibitors potentially useful for the treatment of
asthma, chronic pulmonary obstructive disease and some
autoimmune diseases. These compounds could be devoid of the central side-effects (
nausea,
vomiting,
headache) of the archetypal
Rolipram, which hampered its development as a
drug. The review also highlights the novel structural classes of
PDE 4 inhibitors recently reported in the literature.