Phosphodiesterase-5 inhibitors

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]. 

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Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

Phosphodiesterase Inhibitors (edited by G. Dent, K. Rabe and C. Schudt, forthcoming)... 

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of thrombocytopenia seen with inamrinone. 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

Compare and contrast the benefits and risks for the current phosphodiesterase inhibitors. 

Effectiveness of the three available phosphodiesterase inhibitors is essentially comparable, but differences exist in duration of action, and to a small degree, incidence of side effects and drug interactions. 

TABLE 48-5. Cardiovascular Risk Assessment for Phosphodiesterase Inhibitors... 

Low risk Has asymptomatic cardiovascular disease Has well-controlled hypertension Has mild, stable angina Has mild congestive heart failure (NYHA Class 1) Palient can be started on phosphodiesterase inhibitor... 

High risk Has unstable or symptomatic angina, despite treatment Has poorly controlled hypertension Has severe congestive heart failure (NYHA Class III or IV) Had a recent myocardial infarction or stroke within the past 2 weeks Has moderate or severe valvular heart disease Phosphodiesterase inhibitor is contraindicated... 

Weiss, B. and Hart, W. N., Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents, Annual Review of Pharmacol Toxicol, 17, 441, 1977. 

Wachtel, H. Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3, 5 -monophosphate phosphodiesterase inhibitors. Psychopharmacology. 77 309, 1982. 

Iyo, M., Bi, Y., Hashimoto, K., Inada, T., Fukui, S. Prevention of methamphetamine-induced behavioral sensitization in rats by a cyclic AMP phosphodiesterase inhibitor, rolipram. Eur. J. Pharmacol. 312 163, 1996. 

One of the primary mechanisms for regulation of phosphodiesterase enzyme activity is phosphorylation 374 Phosphodiesterase inhibitors show promise as pharmacotherapeutic agents 374... 

Bara, M., Bourtchouladze, R., Winder, D. G., Golan, H. and Kandel, E. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting longterm potentiation and improves memory. Proc. Natl Acad. Sci. U.S.A. 95 15020-15025,1998. 

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