PDEs, phosphodiesterases selectivity

It is a relatively selective inhibitor of cyclic GMP, cyclic AMP-PDE (phosphodiesterase) type 111 family. It causes vasodilatation with a consequent decrease in systemic vascular resistance. It increases both the force of contraction and velocity of relaxation of cardiac muscles. It is administered IV 0.75 mg/kg/min as a bolus dose followed by 5-10 pg/kg/min IV infusion and total dose not to exceed 10 mg/kg. 

Sildenafil (Viagra ), tadalafil (Cialis ), and vardenafil (Levitra ) act by selectively inhibiting phosphodiesterase (PDE) type 5, an enzyme that breaks down cGMP. By inhibiting the breakdown of cGMP, smooth muscle relaxation is... 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

Indolidan has been shown to be a potent highly selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) located in the sarcoplasmic reticulum [80], being bound more avidly by PDE III than cAMP (Ai = 80 nM)... 

The actions of cAMP are terminated by phosphodiesterases (PDEs) that catalyze the breakdown of cAMP to 5 -AMP (Diunan and Nestler 1999). There are at least 11 different forms of PDEs that are characterized based on their affinity and selectivity for cAMP, as well as cGMP. In addition, the PDEs are differentially regulated by the cyclic nucleotides themselves, by phosphorylation, and by increased expression of certain splice variants (e.g., some isoforms are... 

Phosphodiesterases are a group of enzymes that, among other actions, hydrolyse cAMP. Phosphodiesterase inhibitors are selective for phosphodiesterase III (PDE-III) isoenzyme present in the heart. They prevent the degradation of cAMP, thereby increasing its intracellular concentration (Figure 8.4). This leads to an increase in the intracellular concentration of Ca2+ and an increased contractility and heart rate. PDE-III inhibitors have no adrenoceptor agonistic activity and therefore can be used in combination with other sympathomimetic drugs. They also increase cAMP levels in vascular smooth muscle, but this results in lower intracellular Ca2+ concentrations and thus vasodilatation. 

There is now an ongoing interest to develop highly selective inhibitors also against certain other phosphodiesterases, because general structure-activity relationships can be transferred from one PDE isoenzyme to others [37]. 

The solid phase parallel synthesis of tetrahydroimidazo[l,2-a][l,3,5]triazepin-2-thiones and 2-imines has been reported starting from resin-bound peptides <06JCO127>. Pyrazolo[r,5 l,6]pyrimido[4,5-rf]pyridazinones with potent and selective phosphodiesterase 5 (PDEs) inhibitory activity have been described <06JMC5363>... 

Muller. T. etal. (1996) Subtypes of the pe 4 cAMP phosphodiesterases structure. regulation and selective inhibition. Trends Pharmacol. Set.. 17.294-298. Teixeira, M.M. etal. (1997) Phosphodiesterase (PDE)4 inhibitors antiinflammatory drugs of the future Trends Pharmacol. ScL. 18.164-171. 

PKG and cyclic nucleotide phosphodiesterases (PDEs) (reviewed by Baxter37). A rapid release of natriuretic peptides and induction of their de novo synthesis occurs in myocardial ischemia. Natriuretic peptides may have a cardioprotective role. BNP-32 administration in perfused rat hearts prior to left main coronary artery occlusion and until 30 min of reperfusion resulted in limitation of infarct size in a concentration dependent manner. Furthermore, this effect was abolished by 5-hydroxydecanoate (presumed to be a selective blocker of mitochondrial KATp channels), L-NAME, an inhibitor of NOS and ODQ, a specific soluble guanyl cyclase inhibitor.38 Similarly, human recombinant ANP limited infarct size and reperfusion arrhythmias in a canine model of coronary occlusion and reperfusion.39... 

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