PDE III inhibitor

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]. 

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. 

The extended Electron Distribution (XED) force field was first described by Vinter [96]. This force field proposes a different electrostatic treatment of molecules to that found in classical molecular mechanics methods. In classical methods, charges are placed on atomic centers, whereas the XED force field explicitly represents electron anisotropy as an expansion of point charges around each atom. The author claims that it successfully reproduces experimental aromatic ji stacking. Later, others made similar observations [97]. This force field is now available in Cresset BioMoleculaf s software package [95]. Apaya et al. were the first to describe the applicability of electrostatic extrema values in drug design, on a set of PDE III inhibitors [98]. 

KF-15232, Levosimendan, ORG 20494 (181), Pimobendan (182), Siguazodan (183), SK F 95654, Indolidan (184) and MCI-154 the increased activity seen with the 5-methyl-4,5-dihydro-3(2F/)-pyridazinone PDE III inhibitors is associated with the 5-methyl configuration. Some pyridazinones, such as Zardaverine (185), show combined PDE III and PDE IV inhibitory activity and have been investigated for the treatment of asthma as they may show combined bronchodilatory and antiinflammatory activities. Yet further PDE inhibition, this time of PDE V, is shown by phthalazines like MY 5445 (186). 

Among the combined PDE III/IV inhibitors are zar-daverine. The basis for these compounds includes better bronchodilation (relative to PDE IV inhibitors) and lower cardiovascular effects (relative to PDE III inhibitors). 

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)... 

CYP450 system Anagrelide enhanced the inhibition of platelet aggregation by aspirin and is an inhibitor of cyclic AMP PDE III (may exaggerate the properties of milrinone, enoximone, amrinone, olprinone, and cilostazol). 

Cilostazol (Pletal), a selective inhibitor of PDE III, is used for the treatment of intermittent claudication, an occlusive disease of blood vessels in the legs, which causes pain on walking. It acts as a vasodilator and inhibitor of platelet aggregation. Warfarin, initially developed as a rat poison, and a number of similar compounds, are effective anti-clotting agents by their action as vitamin K antagonists. 

PDE IV inhibitors, as well as some combined PDE IIl/IV inhibitors, are currently under development for the treatment of asthma (Christensen and Torphy, 1994 Nicholson and Shahid, 1994). The basis for this development includes bronchodilatory activity directly related to inhibition of PDE IV, and/or PDE III, in airway smooth muscle, as well as the antiinflammatory activity of these compounds. PDE IV is the major cAMP PDE isozyme present in inflammatory cell types and inhibition of PDE IV has been linked to elevation of cAMP and inhibition of histamine or leukotriene release from mast cells, inhibition of oxygen free radical release from eosinophils or neutrophils, inhibition of adhesion, migration, or activation of eosinophils, and inhibition of TNF-a release from human monocytes (see Nicholson and Shahid, 1994, or Christensen and Torphy, 1994, for some reviews). There are now known to be at least four sub-types of PDE IV that are encoded by different cDNAs (Bolger et al., 1993 Davis et al, 1989 Livi et al., 1990). Although sequence homology of 75-90% is evident among subtypes, key differences, as well as cellular distribution, are apparent. Currently there are no selective inhibitors of the PDE IV subtypes. 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

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