The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure.

Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes known to play a critical role in the indirect regulation of several intracellular metabolism pathways through the selective hydrolysis of the phosphodiester bonds of specific second messenger substrates such as cAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate), influencing the hypertrophy, contractility, apoptosis and fibroses in the cardiovascular system. The expression and/or activity of multiple PDEs is altered during heart failure (HF), which leads to changes in levels of cyclic nucleotides and function of cardiac muscle. Within the cardiovascular system, PDEs 1-5, 8 and 9 are expressed and are interesting targets for the HF treatment. In this comprehensive review we will present a briefly description of the biochemical importance of each cardiovascular related PDE to the HF, and cover almost all the "long and winding road" of designing and discovering ligands, hits, lead compounds, clinical candidates and drugs as PDE inhibitors in the last decade.