Chemistry, biochemistry, and pharmacology of HMG-CoA reductase inhibitors.

After an extensive searching for a microbial product that inhibits cholesterol synthesis, compactin and a series of related metabolites like monacolin K (mevinolin) have been isolated from molds as active agents. These compounds, which were structurally related to hydroxymethylglutaryl coenzyme A, were potent competitive inhibitors of hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition was reversible and the inhibitor constant Ki for compactin was around 10(-9) M. Compactin inhibited cholesterol synthesis in mammalian cells at 10(-9) M. Sterol synthesis in vivo was also reduced when compactin was given orally to rats at a dose of 50 mg/kg. Hydroxymethylglutaryl coenzyme A reductase activity of both cultured cells and rat liver was elevated when sterol synthesis was strongly inhibited by compactin. Both the growth inhibition and reductase induction could be overcome by the presence of mevalonate. A compactin-resistant cell line of mouse FM3A cells, called CR200, was developed by stepwise selection. CR200-cells had an abnormally high level of reductase activity and amplified reductase gene. Compactin was not able to lower plasma cholesterol levels in mice, rats, and hamsters. However, it was highly effective in rabbits, dogs, and monkeys; plasma cholesterol of dogs was reduced by 30%-40% at a dose of 20-50 mg/kg. The low-density lipoprotein cholesterol, which is responsible for atherosclerosis, was preferentially lowered. Compactin was also highly effective in hypercholesterolemic patients at a small dose. The results of the current studies have proved that compactin and related compounds are far more effective in lowering plasma cholesterol than any other drugs available.(ABSTRACT TRUNCATED AT 250 WORDS)