PDE 4 inhibitors: The use of molecular cloning in the design and development of novel drugs

Phosphodiesterase 4 (PDE 4) enzymes are the principal phosphodiesterases responsible for the hydrolysis of cAMP in pro-inflammatory leukocytes. The functional consequences of elevating cAMP in these cells suggests that. inhibition of PDE 4 offers a novel approach to asthma therapy. However, clinical development of early inhibitors has been limited by the side-effect of nausea. In this review, we detail how the molecular biology of the PDE 4 gene family has been integrated with biochemical, cellular and pharmacological studies, This approach has led to the discovery and development of CDP840, a prototype inhibitor for which efficacy has been demonstrated in a clinical model of asthma in the absence of side-effects.