High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients

Int J Impot Res. Jan-Feb 2005;17(1):5-9. doi: 10.1038/sj.ijir.3901283.

Abstract

The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K(m) values of 0.97 microM for cGMP and 2.4 microM for cAMP, and maximal velocities were 4- to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialis, Lilly-ICOS), vardenafil (Levitra, Bayer-GSK), and sildenafil (Viagra, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Carbolines / pharmacology*
  • Cross Reactions
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Humans
  • Imidazoles / pharmacology*
  • Kinetics
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Piperazines / pharmacology*
  • Purines
  • Recombinant Proteins
  • Sildenafil Citrate
  • Substrate Specificity
  • Sulfones / pharmacology*
  • Tadalafil
  • Triazines / pharmacology*
  • Vardenafil Dihydrochloride

Substances

  • Carbolines
  • DNA, Complementary
  • Imidazoles
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Recombinant Proteins
  • Sulfones
  • Triazines
  • Vardenafil Dihydrochloride
  • Tadalafil
  • Sildenafil Citrate
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE11A protein, human
  • PDE5A protein, human
  • Cyclic GMP