Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction

Abstract 5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

[1]  S. Snyder,et al.  Nitric oxide: a physiologic mediator of penile erection. , 1992, Science.

[2]  I. Goldstein,et al.  A nitric oxide-like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. , 1991, The Journal of clinical investigation.

[3]  C. Lugnier,et al.  Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors , 1991, British journal of pharmacology.

[4]  L. Ignarro,et al.  Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission , 1992 .

[5]  K. James,et al.  UK-69,578, a novel inhibitor of EC 3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic. , 1989, Biochemical and biophysical research communications.

[6]  P. J. England,et al.  Inhibitors of cyclic nucleotide phosphodiesterases as therapeutic agents. , 1992, Biochemical Society transactions.

[7]  R. B. Wilson,et al.  Antiallergenic 8-azapurines. 3. Structural characterization of 2-(2-propoxyphenyl)-8-azahypoxanthine, 2-[2-propoxy-5-(propylsulfonyl)phenyl]-8-azahypoxanthine, and 2-[2-propoxy-5-(N-methyl-N-isopropylsulfamoyl)phenyl]-8-azahypoxanthine , 1982 .

[8]  J. Beavo,et al.  Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. , 1990, Trends in pharmacological sciences.

[9]  P. Canniff,et al.  Comparative hemodynamic and renal effects of the low Km cGMP phosphodiesterase inhibitors cicletanine and zaprinast in anesthetized dogs , 1991 .

[10]  J. Beavo,et al.  Multiple cyclic nucleotide phosphodiesterases. , 1994, Molecular pharmacology.