Phosphodiesterase 4 inhibitors, structurally unrelated to Rolipram, as promising agents for the treatment of asthma and other pathologies

An increase of cyclic adenosine and guanosine monophosphate (cAMP and cGMP) level can be achieved by inhibition of phosphodiesterases (PDEs), which ar e the enzymes responsible for the conversion of these second messengers int o the corresponding 5-monophosphate inactive counterparts. The high heterog eneity in PDE families and in their tissue distribution, as well as their d ifferent functional role, make these enzymes very attractive targets for me dicinal chemists. The PDE 4 family is particularly abundant in immunocompet ent cells, where an increase of cAMP leads to the inhibition of the synthes is and release of pro-inflammatory mediators, cytokines and active oxygen s pecies. Moreover PDE 4 inhibitors are able to reduce bronchial smooth muscl e 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 an d corticosteroids, could be replaced by treatment with PDE 4 inhibitors. Th is review mainly covers PDE 4 inhibitors structurally related to xanthines and Nitraquazone, which appear to be very attractive models for the synthes is 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, h eadache) of the archetypal Rolipram, which hampered its development as a dr ug. The review also highlights the novel structural classes of PDE 4 inhibi tors recently reported in the literature. (C) 2000 Editions scientifiques e t medicales Elsevier SAS.