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The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.

A series of alkyltroponylpiperazine derivatives was synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine pathway. The compounds were compared to bromocriptine. The results indicate that dopaminergic activity is very sensitive to small changes in the troponylpiperazine moiety.

Synthesis of a series of thienylethanolamines having varying substituents on the thiophene ring and on the nitrogen atom is described using the general procedure reported earlier. In the determination of their pharmacological profile, some of the derivatives showed marked antihypertensive activity in the spontaneously hypertensive rat model. Tests are also reported which demonstrated that some of these derivatives antagonized alpha- and/or beta-adrenoreceptor activities. The ability of this class of compounds to inhibit catecholamine-induced release of free fatty acids by adipose tissue was demonstrated. Structure-activity relationships in different tests were also determined.

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.

A photoannelation reaction between 2 alpha, beta-unsaturated ketones is described. The photoadduct was isolated and characterized by spectral analysis and was transformed into methoxy and acetoxy derivatives. Some mechanistic implications of photoannelation and the finding of a rearrangement product are discussed. Transformations of diketone to other prostanoic acid derivatives are also described. Structural formulas are depicted in a stepwise manner.