Biochemical aspect of HMG CoA reductase inhibitors.
Subsequent to the discovery of compactin (ML-236B) as a specific inhibitor of HMG CoA reductase, a series of compactin analogs have been either isolated or synthesized. Several of these compounds, which include compactin, mevinolin (monacolin K) and CS-514, have been extensively studied. The inhibition of HMG CoA reductase by these compounds is reversible and competitive (Ki = approximately 1 nM). The 3', 5'-dihydroxypentanoic acid portion of the acid form of compactin analogs, which resembles the HMG portion of HMG CoA, plays a crucial role in inhibitory activity. These inhibitors block sterol synthesis both in cultured mammalian cells and in animals. Strong inhibition of sterol synthesis results in a marked increase in HMG CoA reductase activity both in vitro and in vivo. These compounds strongly lower plasma LDL-cholesterol levels in animals and humans. The lowering of LDL-cholesterol levels occurs by an inhibition of LDL synthesis and/or by an elevation of the receptor-mediated LDL catabolism in the liver.
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Department of Agricultural and Biological Chemistry, Tokyo Noko University, Japan.
Hasumi
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D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C012258:mevastatin; D008148:Lovastatin