Soft drug derivatives related to perhexiline. Part I: In vitro studies

A series of cyclohexylaralkylamines derived from perhexiline was synthesized according to the "soft drug" concept. An amide function was introduced as a labile centre to give non-toxic moieties in vivo after the "soft drugs" had attained their therapeutic aims. Compounds were evaluated for their alpha-adrenolytic, calcium antagonist and vasodilator activities in vitro. Some of them, 2, 3, 7 and 15 on rat aorta had alpha-adrenolytic effects comparable to that of perhexiline. Most of them were about 10 times more active calcium antagonists on depolarized pig coronary artery than perhexiline. All derivatives produced concentration-related coronary dilation in the perfused guinea pig heart. Compound 2 was equipotent to perhexiline. The decrease in coronary resistance might, at least partly, be attributable to the alpha-blocking properties of the molecules. In conclusion, the introduction of an amide function into the perhexiline skeleton does not markedly alter the in vitro pharmacological properties.