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Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway. Phosphodiesterase 5 (PDE5) is widely expressed in several tissues in the body for example brain, lung, kidney, urinary bladder, smooth muscle and platelets.〔 It is possible to prevent cGMP hydrolysis by inhibiting PDE5 and therefore treat diseases associated with low cGMP levels, because of this, PDE5 is an ideal target for the development of inhibitors. The three major PDE5 inhibitors are sildenafil, tadalafil and vardenafil.〔 ==Discovery== PDE5 is an enzyme that was first purified in 1980 from a rats lung. PDE5 converts intracellular cGMP to the nucleotide GMP. Many tissues contain PDE5, such as lungs, kidneys, brain, platelets, liver, prostate, urethra, bladder and smooth muscles. Because of the localization of PDE5 in the smooth muscle tissue, inhibitors were developed for the treatment of erectile dysfunction along with pulmonary hypertension.〔〔 Sildenafil was initially introduced for clinical trial in 1989. It was the result of extensive research on chemical agents targeting PDE5 that could be effective in treatment of coronary heart disease. Sildenafil did not prove effective for coronary heart disease but an interesting side effect was discovered, a penile erection. That side effect soon became the main field of investigation. The inhibitor is highly selective for the PDE5 family.〔 Sildenafil is a prototype of PDE5 inhibitors that Pfizer launched as Viagra. It was approved by the Food and Drug Administration (FDA) in 1998 as the first oral medicine for erectile dysfunction. Later, in the year 2005, it was approved for the treatment of pulmonary arterial hypertension.〔 Vardenafil and tadalafil were discovered in 1990. These drugs came out of research programs focusing on finding PDE5 inhibitors for the treatment of cardiovascular diseases and erectile dysfunction.The two PDE5 inhibitors soon became treatments for these conditions.〔〔 Tadalafil is the most versatile inhibitor and has the longest half-life, 17,5 hours. This allows for a longer therapeutic window and is therefore often a more convenient drug than others with a shorter therapeutic window. Tadalafil is more bioavailable (80%) than sildenafil (40%) and vardenafil (15%) but it has a slow absorption, or about 2 hours compared to 50 minutes of sildenfil. Vardenafil is most known for its potency. Because of severe adverse affects and patients dissatisfaction with current therapy choices other inhibitors have recently been approved for clinical use. These inhibitors are udenfil, avanafil lodenafil and mirodenafil. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Discovery and development of phosphodiesterase 5 inhibitors」の詳細全文を読む スポンサード リンク
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