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J M Lind

Publications and source records attributed to J M Lind.

6 recordsLinked to original sources
PubMed1992

Synthesis, cardiac electrophysiology, and beta-blocking activity of novel arylpiperazines with potential as class II/III antiarrhythmic agents.

A series of novel arylpiperazines have been prepared in an attempt to incorporate both class II (beta-receptor blocking) and class III antiarrhythmic properties in a single molecule. The key step in the preparation of the new compounds involves a regioselective heterocyclic ring formation. All but four compounds significantly prolonged action potential duration in canine cardiac Purkinje fibers (class III activity). All but one of the compounds demonstrated beta-receptor affinity in a competitive binding assay and three had beta 1-receptor selectivity. Compared to sotalol, a reference class II/III agent, arylpiperazine 7a (4-[(methylsulfonyl)amino]-N-[(4- phenylpiperazin-2-yl)methyl]benzamide) demonstrated beta 1-selectivity and was 1 order of magnitude more potent in the in vitro class III and the beta 1-receptor screens. Compound 7a was evaluated further and found to be effective in preventing programmed electrical stimulation-induced arrhythmias in conscious dogs (class III activity) and against epinephrine-induced arrhythmias in halothane anesthetized dogs (class II activity).

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PubMed1990

Synthesis and cardiac electrophysiological activity of aryl-substituted derivatives of the class III antiarrhythmic agent sematilide. Potential class I/III agents.

Twelve novel derivatives of the selective class III antiarrhythmic agent sematilide were prepared in an attempt to incorporate both class I and class III electrophysiological properties into a single molecule. Electrophysiological activity was determined by standard microelectrode techniques in canine cardiac Purkinje fibers. Initial assessment of class I efficacy was carried out in a ouabain-induced arrhythmia model in guinea pigs. All of the compounds prolonged action potential duration in Purkinje fibers (class III activity), and three were active against ouabain-induced arrhythmias (class I activity). Selected compounds were evaluated further in dogs for efficacy against arrhythmias occurring 24 h following coronary ligation (automatic arrhythmias) and induced by using programmed electrical stimulation techniques (reentrant arrhythmias). The most effective compounds from the series are 3g and -j, which were effective in both canine models. Molecular modeling and structure-activity relationships are discussed.

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PubMed1990

Synthesis of novel (aryloxy)propanolamines and related compounds possessing both class II and class III antiarrhythmic activity.

Several (aryloxy)propanolamines and related compounds (i.e. 5-13, 16-18, 20-24, 27-33, 35, 37-39, 41, and 42) were synthesized and investigated for their class III electrophysiological activity and class II (beta-blocking) effects with use of in vitro and in vivo models. Structure-activity relationships are discussed for a series of 30 compounds. A number of these compounds prolonged the action potential duration at 95% repolarization of isolated canine cardiac Purkinje fibers by 20% (C20APD95) at concentrations of less than 1.0 microM, with no significant effects on cardiac conduction. beta-Adrenergic receptor binding studies showed that some of these compounds were 2-20 times more potent for cardiac beta 1 receptors than for beta 2 receptors. In particular, compounds 32, 41, 1, and especially (S)-1 were found to be orally active class III agents in anesthetized mongrel dogs (1 or 3 mg/kg, id) and efficacious at suppressing programmed electrical stimulation induced arrhythmias in halothane-anesthetized dogs. The profile of these compounds was similar to that found for sotalol. Compound (S)-1, which was more potent than sotalol in the PES study and equieffective in the halothane/epinephrine dog model, is being investigated further as a combined class III/II antiarrhythmic agent.

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