Discovery of phosphodiesterase-4 inhibitors: Serendipity and rational drug design

Phosphodiesterase 4 (PDE4), the primary cyclic AMP-hydrolysing enzyme in cells, is a promising drug target for a wide range of mental disorders including Alzheimer s and Huntington s diseases, schizophrenia, and depression, plus a range of inflammatory diseases including chronic obstructive pulmonary disease, asthma, and rheumatoid arthritis. However, targeting PDE4 is complicated by the fact that the enzyme is encoded by four very closely related genes, together with 20 distinct isoforms as a result of mRNA splicing, and inhibition of some of these isoforms leads to intolerable side effects in clinical trials. With almost identical active sites between the isoforms, X-ray crystallography has played a critical role in the discovery and development of safer PDE4 inhibitors. Here we describe our discovery of a novel class of highly potent PDE4 via a virtuous cycle of structure-based drug design and serendipity.