Inhibitors of PDE1 and PDE5 cGMP phosphodiesterases: patents and therapeutic potential

Cyclic 3′5′-guanosine monophosphate (cGMP) is a key second messenger involved in the processes of intracellular signalling. Steady state levels of cGMP are modulated through a balance between the rates of formation and degradation of the nucleotide. A potential therapeutic approach to manipulation of cGMP is the inhibition of the phosphodiesterases PDE1 and PDE5. PDE5 inhibitors have been targeted by many companies and have resulted in a large number of patents. The disclosed inhibitors cover an eclectic range of polycyclic nitrogen heterocycles. Activities reported show IC50 values in the low nanomolar to subnanomolar range. A wide range of tissue, cellular and in vivo effects are also reported for these PDE5 inhibitors. By contrast, only a very few patents have appeared which claim PDE1 inhibitory activity. The potential use of PDE1 and PDE5 inhibitors in the treatment of coronary artery disease, hypertension, congestive heart failure, erectile dysfunction and pulmonary hypertension is discussed.