Pharmacology of CRE‐1087, A New Antiarrhythmic Drug

Abstract

CRE-1087, 1 -( 2-methoxy)-phenoxy-2,3 -bis[ 2-diethylamino-etox yI-propane dicitrate (Fig. l), is a new class Ic antiarrhythmic drug first synthetized in 1978 (1) in the Molecular Research Center of the Cermol Pharmaceutical Division. It can be administered either orally or intravenously. This agent was selected for clinical testing from a chemical series of related glycerol-aminoalkylethers on the basis of its superior antiarrhythmic activity and high safety ratio in both the parenteral and oral dosage forms.CRE-1087 crystallized as a white solid (molecular weight 780.80) with a melting point of 79-83'. It is soluble in water to the extent of about 35%, as a base it is soluble in ethanol, chloroform, dichloromethane, and in common organic solvents. PRECLINICAL STUDIES Electrophysiological Effects in Isolated Cardiac PreparationsMicroelectrode recordings have been used to study the effects of CRE-1087 on the transmembrane potentials of guinea pig atrial and ventricular muscle fibers under a variety of conditions (8,9,10,13,37). At concentrations between 0.1 and 100 pA4 CRE-1087 decreased in a concentration-dependent manner the amplitude, overshoot, and maximal rate of depolarization ( V , , , an index of the fast inward sodium current) of the atrial and ventricular action potentials, and slowed intraventricular conduction velocity. In microelectrode studies in guinea pig papillary muscles CRE-1087 was more potent than quinidine (43), propafenone (41), flecainide (12), or mexiletine (12,41,43) in inhibiting the V,,,. However, at all these concentrations CRE-1087 had no effect on either the resting membrane potential or the action potential duration measured at both 50% (APD,,) and