Phosphodiesterase type 5 inhibitors: molecular pharmacology and interactions with other phosphodiesterases.
Erectile function is determined by tight regulation of relaxation or contraction of corpus cavernosal smooth muscle, which is the result of a long and complex chain of molecular events. Control of erectile function resides in signaling pathways of the central and peripheral nervous system, as well as intracellular events in the penile smooth muscle. Vascular events resulting in erection have long been understood, and the role of the signaling pathways of the central and peripheral nervous systems in erectile function and dysfunction has become increasingly clear over the last decade. This knowledge has led to the development and current availability of effective oral treatments for erectile dysfunction, the selective phosphodiesterase type 5 (PDE5) inhibitors-sildenafil, vardenafil and tadalafil. In the past few years we have seen an elucidation of the molecular events involved in erectile function and dysfunction and the detailed mechanisms of action by which the specific PDE5 inhibitors work. A review of those mechanisms helps to explain the success of the currently available PDE5 inhibitors and the differences between them and suggests new approaches for developing potential future novel therapies or refinements to existing structures that may improve their efficacy, selectivity and safety profiles.
Seftel
Allen D
AD
Professor of Urology and Reproductive Biology, Department of Urology, Case Western Reserve University, School of Medicine, 11100 Euclid Ave, Cleveland, OH 44106-5046, USA. ads6@po.cwru.edu
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology; D006152:Cyclic GMP / Q000737:chemistry; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004347:Drug Interactions; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology; D000068581:Tadalafil; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
D002243:Carbolines; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP