PDE5 phosphodiesterase type

PDE5 phosphodiesterase type 5 drugs used to treat conditions such as erectile dysfunction, e.g., sildenafil, interfere with this enzyme... 

FIGURE 60.1 Mechanism of action of sildenafil in corpus cavernosal smooth muscle cells. NANC Non-adrenergic, noncholinergic NO nitric oxide PDE5 Phosphodiesterase Type 5. 

Phosphodiesterase Type 5 (PDE5) inhibitors sildenafil citrate... 

The approved drugs for erectile dysfunction (ED) all share the same mode of action, which is inhibition of phosphodiesterase type 5 (PDE5). PDE5 hydrolyzes the phosphodi-ester of cyclic GMP (cGMP). Elevated levels of cGMP relax the muscle tissue that lines the blood vessels of the corpus cavernosum in the penis. Blood freely enters the tissue,... 

A very convincing example of the usefulness of benzologues is provided by the synthesis of compound A, a linear benzologue of the prototypical phosphodiesterase type 5 (PDE5) inhibitor zaprinast, and its optimization to potent and selective PDE5 inhibitors such as compound B [11] (Fig. 1.4). 

Another recent example is provided by the discovery of the use of sildenafil (Viagra Fig. 1.15), a phosphodiesterase type 5 (PDE5) inhibitor, as an efficacious, orally active agent for the treatment of erectile dysfunction [25,26]. Initially, this compound was brought to the clinic as an hypotensive and cardiotonic substance, but its usefulness in erectile dysfunction resulted unexpectedly from clinical observations made during a 10-day toleration study in Wales [27]. 

Fig. 28 Inhibitory cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) flavonoids from Sophora flavescens...

Haning, H., Niewoehner, U., Bischoff, E. (2003) Phosphodiesterase Type 5 (PDE5) Inhibitors. Progress in Medicinal Chemistry 41,246-306. 

Devan B, Duffy K, Bowker J et al (2005) Phosphodiesterase type 5 (PDE5) inhibition and cognitive enhancement. Drugs Future 30 725... 

Rg. 5.21 Structure of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil. ... 

Nitrovasodilators see Chapter 31) produce vasodilation by NO-dependent elevation of cychc GMP in vascular smooth muscle. The pharmacologic effects of sildenafil, tadalafil, and vardenafil result from inhibition of the type 5 cyclic nucleotide phosphodiesterase (PDE5) that hydrolyzes cyclic GMP to 5 GMP in the vasculature. Thus, coadministration of an NO donor e.g., nitroglycerin) with a PDE5 inhibitor can cause potentially catastrophic hypotension. 

Since the discovery of sildenafil for the treatment of ED in 1993, two additional products, vardenafil and tadalafil, have been introduced to the market [6, 7]. All these three drugs work by inhibiting type 5 phosphodiesterase (PDE5). This inhibition increases the amount of cyclic guanosine monophosphosphate (cGMP), which... 

---