PDE-4 INHIBITORS - THE USE OF MOLECULAR-CLONING IN THE DESIGN AND DEVELOPMENT OF NOVEL DRUGS

Phosphodiesterase 4 (PDE 4) enzymes are the principal phosphodiesteras es responsible for the hydrolysis of cAMP in pro-inflammatory leukocyt es. The functional consequences of elevating cAMP in these cells sugge sts that. inhibition of PDE 4 offers a novel approach to asthma therap y. However, clinical development of early inhibitors has been limited by the side-effect of nausea. In this review, we detail how the molecu lar biology of the PDE 4 gene family has been integrated with biochemi cal, cellular and pharmacological studies, This approach has led to th e discovery and development of CDP840, a prototype inhibitor for which efficacy has been demonstrated in a clinical model of asthma in the a bsence of side-effects.