New PDEs Inhibitors for Erectile Dysfunction

Phosphodiesterases (PDEs) are functionally diverse enzymes with wide organ and tissue distributions. Of these enzymes, PDE₅ has received particular attention largely because of the introduction and widespread use of the selective PDE₅ inhibitor sildenafil citrate (Viagra®) as an oral therapy for erectile dysfunction(ED). Within the corpus cavernosum of the penis, PDE₅ influences regulation of vascular and trabecular smooth muscle contractile tone by enzymatically degrading the cyclic 3',5'-guanosine monophosphate(cGMP), the key second messenger. By reversibly inhibiting this enzymatic activity, the competitive inhibitors of PDE₅, including sildenafil and newly introducing tadalafil(Cialis™) and vardenafil(Lebitra™) act as potent 'agonists' of the erectile response. Data from separate 12-week multicenter, randomized, double-blind, placebo-controlled trials involving sildenafil, as well as tadalafil and vardenafil, have demonstrated that approximately 80% (or more) of men reported improved erections after treatment with each of these PDE₅ inhibitors at the upper end of the dosing range. PDE₅ inhibitors have been well tolerated. In clinical studies, vasodilator effects(e.g. headache and flushing) have generally been mild, transient, and infrequently associated with premature study discontinuation. The present article reviews the characteristics of new PDE₅ inhibitors in experimental and clinical studies.