Selective phosphodiesterase inhibitors

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. 

Phosphodiesterase inhibitors are selective for isoenzyme type 5 in genital tissue. Inhibition of this isoenzyme in nongenital tissues (e.g., peripheral vascular tissue, tracheal smooth muscle, and platelets) can produce adverse effects. 

Horowski, R. and SastreHernandez, Y.M., Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients global evaluation of the preliminary reports, Curr. Ther. Res. Clin. Exp., 38, 23, 1985. 

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

PEE-IV Inhibitors Selective inhibitors of phosphodiesterase IV (PDE4) are in development for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Two of them contain fluorine atoms roflumilast (preregistered) bears a difluoromethyl ether and AWD-12-281 (Phase II) has a single fluorine atom (Figure 8.51). 

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. 

Manallack, D. T., Hughes, R A., Thompson, P. E. (2005) The next generation of phosphodiesterase inhibitors structural clues to ligand and substrate selectivity of phosphodiesterases. J Med Chem 48(10), 3449-3462. 

A more recent example is that of sildenafil which, as a result of observations made during Phase I studies in male volunteers, is now used to treat erectile dysfunction. Sildefanil had originally been designed as an analogue of zaprinast, and a more selective phosphodiesterase inhibitor (PDE5) for use as a cardiovascular agent (see Chapter 1-1). 

Phosphodiesterase inhibitors, which prolong the action of cyclic nucleotides, have been the targets for the development of therapeutically useful compounds. Several selective inhibitors of this class of enzymes have been identified and some are under development for therapeutic purposes (Beavo and Reifsnyder, 1990 Corda et al, 1990). 

The phosphodiesterase inhibitors, enoximone and milrinone have positive inotropic effect due to selective myocardial enzyme inhibition and may be used for short-term treatment of severe congestive cardiac failure. Evidence from longer term use indicates that these drugs reduce survival. 

Other drugs may also have an inhibitory effect on cytokine synthesis. Elevation of cyclic AMP has an inhibitory effect on ID2 release from lymphocytes in vitro (Didier et al., 1987) and this may be achieved by theophylline at high plasma concentrations. Selective phosphodiesterase inhibitors may also be effective and recently phosphodiesterase IV inhibitors have been demonstrated to inhibit the release of IL-4 and IL-5 from T lymphocytes in vitro (Essayan et al., 1993). 

Phosphodiesterase Inhibitor - CK-0383 ( ) was I70 X more potent and 5 more selective than theophylline tested in guinea pig trachea and atrium in vitro possibly indicating phosphodiesterase selectivity. 

Ke, H., Wang, H. Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. Curr. Top. Med. Chem. 2007, 7, 391-403. 

Ruckstuhl, M. Beretz, A. Anton, R. Landry, Y., Flavonoids are selective cyclic GMP phosphodiesterase inhibitors, Biochem. Pharmacol, 1979, 28, 535-538. 

Huai, Q., Liu, Y., Francis, S.H., Corbin, J.D., and Ke, H. (2004) Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J. Biol. Chem. 279, 13095-101. 

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