Soft drug derivatives related to perhexiline. Part II: In vivo studies

Abstract

A series of cyclohexylaralkylamines derived from perhexiline and synthesized according to the "soft drug" concept were evaluated for haemodynamic effects and myocardial oxygen consumption in vivo. In anaesthetized rabbits, the most active compounds, 2, 5, and 11 decreased arterial blood pressure, to a greater extent dp/dtmax and, to a lesser extent heart rate. The decrease in cardiac work and the decrease in cardiac output varied concomitantly. The cardiac effort index decreased in all cases to a greater degree than with perhexiline. In anaesthetized open-chest dogs, the potential antianginal properties of compounds 2, 5 and 11 were due to a decrease in cardiac work via a decrease in cardiac output and myocardial oxygen consumption. None of these compounds reduced arterial blood pressure. Compounds 2 and 5 decreased myocardial oxygen consumption more than perhexiline. Compound 5 was the most promising molecule of this series both as regards cardiac work and myocardial oxygen consumption, being active at a lower dose than perhexiline and having a long active span. These studies suggest that compounds 2, 5 and 11 might be beneficial to patients with angina pectoris.