Ingeborg Lues

Synthesis and biological activities of meribendan and related heterocyclic benzimidazolo-pyridazinones

Abstract The synthesis of new heterocyclic benzimidazolo-pyridazinones is described. The new compounds were evaluated as inotropic agents with ‘calcium-sensitizing’ effects. 5-Methyl-6-[2-(3-pyrazolyl)-5-benzimidazolyl]-2,3,4,5-tetrahydro-pyridazin-3-one hydrochloride (meribendan) turned out to be the most interesting compound and was chosen for development as a positive inotrope.

Preparation of the enantiomers of the novel CA-sensitizer EMD 53 998

Abstract Both enantiomers of EMD 53 998 (1), a novel cardiotonic with Ca-sensitizing activity, were readily prepared by kinetic resolution of the N-acylthiadiazinone 2. The Ca-sensitizing effect is highly stereospecific and resides in the (+)-enantiomer. The (−)-entantiomer is a pure PDE inhibitor devoid of any Ca-sensitizing activity.

3-substituted 6-butyl-1,2-dihydropyridin-2-ones: A new series of potent nonpeptide angiotensin II receptor antagonists

Abstract The syntheses and biological activities of a series of novel 3-substituted 6-butyl-1,2-dihydro-pyridin-2-ones are presented. A number of these compounds are shown to be potent antagonists of angiotensin II with in vitro potencies in the nanomolar or even subnanomolar range. They also have proven their suitability as effective inhibitors of angiotensin II pressor response in vivo.

STEREOSELECTIVITY OF THE POSITIVE INOTROPIC EFFECTS OF NEWER DIAZINONE-CARDIOTONICS

Abstract In 5-methyl-dihydropyridazinones, a stereoselectivity is observed only with respect to the phosphodiesterase III-inhibition. The (−)-enantiomers are very strong inhibitors whereas their (+)-counterparts exhibit only a weak activity. In the case of the thiadiazinone EMD 53998 a pronounced stereoselectivity regarding Ca-sensitivity and phosphodiesterase inhibition is apparent. It is concluded that Levosimendan exerts its positive inotropism almost exclusively through its potent phosphodiesterase III-inhibitory effect.

Characterization of a novel K+ channel activator, EMD 52962, in electrophysiological and pharmacological experiments

Introduction Recent publication have indicated that some benzopyran derivatives (e.g. cromakalim) are potent relaxants of a number of smooth muscles. Their main pharmacological properties are most probably related to their ability to hyperpolarize the membranes of smooth muscle cells by increasing the conductance to potassium ions (Hamilton et al. 1986). We have therefore explored the possibility that a newly synthetised derivative, EMD 52692 (4-(1,2-dihydro-2-oxo1 -pyridyl)-2,2-dimethyl-2H1-benzo pyran-6-carbonitrile), also induces vascular relaxation by a similar mechanism.