title: Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction.
abstract: Soluble guanylate cyclase (sGC) is an important enzyme in corpus cavernosum smooth muscle cells as it is one of the regulators of the synthesis of cGMP. The efficacy of sildenafil (Viagra) in the treatment of male erectile dysfunction indicates the importance of the cGMP system in the erectile response as the increased levels of cGMP induce relaxation of the corpus cavernosum. sGC is physiologically activated by nitric oxide (NO) during sexual stimulation, and its activity can be pharmacologically enhanced by several NO-donors. Agents like YC-1 can also activate sGC after binding to a novel allosteric site in the enzyme, a site different from the NO binding site. YC-1 can relax rabbit cavernosal tissue and it facilitates penile erection in vivo. This review summarizes the enzymology, biochemistry and pharmacology of this novel allosteric site and its relevance for the regulation of penile function. This type of sGC activators represent a new class of compounds with a different pharmacological profile in comparison to the classical NO-donors and they could be beneficial for the treatment of male erectile dysfunction.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. jorge.brioni@abbott.com
authors.forename: J D
authors.initials: JD
authors.lastname: Brioni
authors.forename: M
authors.initials: M
authors.lastname: Nakane
authors.forename: G C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: R B
authors.initials: RB
authors.lastname: Moreland
authors.forename: T
authors.initials: T
authors.lastname: Kolasa
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: D000495:Allosteric Site; D000818:Animals; D020536:Enzyme Activators / Q000627:therapeutic use*; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D012995:Solubility
chemical_list: D020536:Enzyme Activators; D007191:Indazoles; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D006162:Guanylate Cyclase