Trapidil derivatives as potential antiatherosclerotic drugs.

Trapidil, a triazolopyrimidine, and its derivatives are coronary vasodilating drugs. Trapidil reduces the serum level of low density lipoprotein- and very low density lipoprotein-cholesterol and increases the serum level of high density lipoprotein-cholesterol in hyperlipemic patients. The present study demonstrates that trapidil and five different trapidil derivatives inhibit the proliferation of cells cultured from grossly normal intima and fatty streaks of human aorta. The inhibiting effect of trapidil derivatives is about 60%, similar to the standard substance 3-isobutyl-1-methyl-xanthine (MIX). In cells cultured from atherosclerotic plaques trapidil and trapidil derivatives reduced the content of cholesteryl esters by 36% for trapidil and between 47% and 68% for 4 of 5 trapidil derivatives, respectively. The trapidil derivative AR 12463 (5-piperidino-7-[N-(n-amyl)-N-(beta-hydroxyethyl)amino]-s-triazolo[1,5- a]pyrimidine) reduces the free cholesterol content by 29%, but the other trapidil derivatives are without effect on this parameter. Four of five derivatives decrease the content of triglycerides by 53 to 70%. The synthesis of collagen is inhibited by the trapidil derivative AR 12463 (25%). Trapidil and other derivatives have a smaller or no effect on the synthesis of collagen. These effects of trapidil derivatives point to potential antiatherosclerotic properties. The possible mechanisms are discussed.