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

doi:doi:10.1038/sj.ijir.3901283

International Journal of Impotence Research homepage

International Journal of Impotence Research (2005) 17, 5–9. doi:10.1038/sj.ijir.3901283 Published online 11 November 2004

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

J L Weeks II¹, R Zoraghi¹, A Beasley¹, K R Sekhar², S H Francis¹ and J D Corbin¹

¹Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, Nashville, Tennessee, USA
²Vanderbilt Center for Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Correspondence: JD Corbin, Department of Molecular Physiology and Biophysics, Light Hall Room 702, 21st & Garland, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA. E-mail: jackie.corbin@vanderbilt.edu

Received 21 July 2004; Revised 5 October 2004; Accepted 5 October 2004; Published online 11 November 2004.

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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 M for cGMP and 2.4 M 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.