The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function

Abstract

SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts AL6 9AR 1 SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 g1M. The IC50 values were greater than 100 1M for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 1M) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 LM). 2 In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3 Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dpldtM,, in the range 10-50 tg kg-'. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtma, were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4 SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (ICm = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5 The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets. 6 Collagen-induced aggregation of rat PRP was also inhibited by SK&F 95654 (ICso = 65 nM). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg-', SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI-PDE inhibitors studied (siguazodan and SK&F 94120). 7 In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine-or U46619-induced bronchoconstriction in the anaesthetized, ventilated guinea-pig. 8 Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.

Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors

“…1 PDE3 inhibitors have been investigated clinically for their cardiotonic properties (vasodilation and inotropic activity) and antithrombotic properties. 2 Research in this field has led to the discovery of some well described isozyme selective PDE3 inhibitors like milrinone (1), 3 cilostamide (2), 4 SK&F 95654 (3), 5 and NSP-513 (4). 6 To date, two highly homologous subtypes of PDE3 have been identified and each of these subtypes is localized in different tissues.…”

Mesenteric Arteriopathy in the Rat Induced by Phosphodiesterase III Inhibitors: An Investigation of Morphological, Ultrastructural, and Hemodynamic Changes

“…Phosphodiesterase III (PDE III) inhibitors are potent inotropic/vasodilators due to inhibition of the cGMP-inhibitable isozyme of phosphodiesterase with consequent elevation of [cAMP]i in cardiac myocytes and vascular smooth muscle (11,24,33,34,36). PDE III inhibitors induce an epicardial arteriopathy in the dog following multiple administration of these compounds at suprapharmacological doses (13).…”

Synthesis of new 4,5-3(2H)pyridazinone derivatives and their cardiotonic, hypotensive, and platelet aggregation inhibition activities

“…So, at first, compound 12a was used in 0.6 µM/20 µL and 1.5 µM/ 50 µL respectively, then compound 16d was tested using smaller concentrations 0.1 µM/50 µL and 0.04 µM/20 µL respectively. After the addition of 2.5 µM adenosine diphosphate (ADP) used as platelet activating factor (PAF), aggregation was determined, before and after addition of the test compounds, by the change in absorbance monitored for 4 min (Murray et al, 1992). Experiments were repeated on three samples …”

“…with the smaller one, which is also considered as a neglected percent. Test was done as described in the experimental protocol using ADP as platelet activating factor PAF on platelet rich plasma (Murray et al, 1992) of human volunteers. It is worth noting that increasing concentration of PAF from 2.5 µM to 5 µM showed no effect on platelet aggregation inhibition percent observed with the test compounds.…”