Norbert Beier

The novel cardiotonic agent EMD 53 998 is a potent calcium sensitizer

EMD 53 998, a novel thiadiazinone derivative, increases the contractile force of cardiac tissue in vitro through both an inhibition of phosphodiesterase III (PDE III) and a sensitization of cardiac contractile proteins to Ca2+. Guinea pig ventricular PDE III is selectively inhibited by EMD 53 998 (IC50 = 60 nM) without major effects on other PDE isoenzymes. Consonant with this is an increase in cAMP content of rat ventricular cells and a potentiation by EMD 53 998 of the cAMP-elevating action of isoprenaline (increase by 50% at 1.3 μM). Sensitization to Ca2+ by EMD 53 998 (3–30 μM) finds its expression in a leftward shift of the Ca2+ response curve for force generation in skinned fibers from porcine ventricular muscle and failing human heart as well as for activation of bovine cardiac myofibrillar actomyosin ATPase. Interestingly, EMD 53 998 elevates the maximum of the Ca2+ -response curve for both parameters. Pimobendan studied under identical conditions was 100 times less potent than EMD 53 998. EMD 53 998 increases force development of guinea pig papillary muscle in a concentration-dependent manner with an EC50 of 3.6 μM. thus being 10 times more potent than pimobendan. In contrast to pimobendan, the positive inotropic effect of EMD 53 998 is barely affected by carbachol. Further evidence for a Ca2+ -sensitizing effect of EMD 53 998 is provided by an additional increase in force generation in the presence of supramaximal isoprenaline concentrations. It is concluded that the positive inotropic action of EMD 53 998 is mediated through both cAMP-independent and cAMP-dependent mechanisms, with the former probably prevailing. We are not aware of other compounds with a similarly high Ca2+ -sensitizing potency. On these grounds, EMD 53 998 appears to be a promising inotropic agent.

(6-oxo-3-pyridazinyl)-benzimidazoles as potent angiotensin II receptor antagonists

The syntheses and angiotensin II antagonistic activities of novel (6-oxo-3-pyridazinyl)-benzimidazole derivatives are reported. Evaluation of the structure-activity relationships led to the discovery of potent orally active antihypertensive compounds.

URACIL-BASED ANGIOTENSIN II RECEPTOR ANTAGONISTS

1,2,3,4-Tetrahydro-2,4-pyrimidinedione (uracil) is a valuable nucleus for the construction of potent antagonists of the AT1 angiotensin II receptor. Various synthetic routes were applied in order to introduce a wide range of different groups at the N3-nitrogen and to obtain condensed uracil derivatives as well. 121 with a N,N-dimethylacetamide residue at N3 was the most potent compound with an IC50 of 0.65 nM.