High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients.
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.
Weeks
J L
JL
Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0615, USA.
Zoraghi
R
R
Beasley
A
A
Sekhar
K R
KR
Francis
S H
SH
Corbin
J D
JD
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002243:Carbolines / Q000494:pharmacology*; D003429:Cross Reactions; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011994:Recombinant Proteins; D000068677:Sildenafil Citrate; D013379:Substrate Specificity; D013450:Sulfones / Q000494:pharmacology*; D000068581:Tadalafil; D014227:Triazines / Q000494:pharmacology*; D000069058:Vardenafil Dihydrochloride
D002243:Carbolines; D018076:DNA, Complementary; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011994:Recombinant Proteins; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C406737:PDE11A protein, human; C517381:PDE5A protein, human; D006152:Cyclic GMP