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

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