Inhibition of Cyclic Nucleotide Phosphodiesterases by Methylxanthines and Related Compounds

Abstract

Naturally occurring methylxanthines were the first inhibitors of cyclic nucleotide (cN) phosphodiesterases (PDEs) to be discovered. To improve potency and specificity for inhibition of various PDEs in research and for treatment of diseases, thousands of compounds with related structures have now been synthesized. All known PDE inhibitors contain one or more rings that mimic the purine in the cN substrate and directly compete with cN for access to the catalytic site; this review focuses on inhibitors that contain a nucleus that is closely related to the xanthine ring of theophylline and caffeine and the purine ring of cNs. The specificity and potency of these compounds for blocking PDE action have been improved by appending groups at positions on the rings as well as by modification of the number and distribution of nitrogens and carbons in those rings. Several of these inhibitors are highly selective for particular PDEs; potent and largely selective PDE5 inhibitors are used clinically for treatment of erectile dysfunction [sildenafil (Viagra™), tadalafil (Cialis™) and vardenafil (Levitra™)] and pulmonary hypertension [sildenafil (Revatio™) and tadalafil (Adenocirca)]. Related compounds target other PDEs and show therapeutic promise for a number of maladies.

Identification of Amino Acid Residues Responsible for the Selectivity of Tadalafil Binding to Two Closely Related Phosphodiesterases, PDE5 and PDE6

“…K m values are the average of at least 2 independent experiments (Ͻ20% variation). Kinetic parameters for the wild-type enzyme are within the range reported in the literature, whereas the K i value for vardenafil under our experimental conditions was ϳ10-fold higher (see "Experimental Procedures") than previously reported (41).…”

Type 2 cGMP-dependent protein kinase regulates homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium

“…The ability of the PDE-5 inhibitor Vard to increase cGMP levels and activate protective PKG2-mediated signaling in the colon epithelium therefore has significant translational potential. As several PDE-5 inhibitors are already used in the clinic to treat erectile dysfunction and pulmonary hypertension, 33 the present results highlight additional therapeutic potential for these drugs in gastrointestinal diseases.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…For inhibition of cAMP-degrading phosphodiesterases (PDEs), cell-free AC assays often contain the PDE inhibitor isobutylmethylxanthine (IBMX). However, limited water solubility of the inhibitor (unless aqueous solutions are preheated or organic solvents are used) and IBMX resistance of certain PDEs (Bender and Beavo, 2006;Francis et al, 2011) could influence assay results. Other studies included cAMP (see, e.g., Gille et al, 2004), but cAMP at high concentrations can inhibit ACs are obtained (Gille et al, 2004: Mou et al, 2005, the affinities of inhibitors increase (Gille et al, 2004;Mou et al, 2005) and the pharmacological profile of diterpenes is affected (Erdorf et al, 2011).…”