Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.
Alfred W. Alberts,Julie S. Chen,G Kuron,V Hunt,Jesse W. Huff,Carl H. Hoffman,John W. Rothrock,Lopez Maria B,Henry Joshua,Elbert E. Harris,Arthur A. Patchett,R L Monaghan,S Currie,E Stapley,George Albers-Schonberg,Otto D. Hensens,J Hirshfield,Karst Hoogsteen,Jerrold M. Liesch,James P. Springer +19 more
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It was shown that mevinolin was an orally active cholesterol-lowering agent in the dog and orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay.Abstract:
Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.read more
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References
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Inhibitory Effects on Lipid Metabolismn in Cultured Cells of ML‐236B, a Potent Inhibitor of 3‐Hydroxt‐3‐methylglutaryl‐Cornzyme‐A Reductase
TL;DR: It is concluded slight activity of endogenous sterol synthesis, which provides enfogenous copounds generated from meavalonate, may be essential to the growth of cells even when sufficeient amounts of cholesterol are availavel to the cells.
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Therapeutic effects of ML-236B in primary hypercholesterolemia
TL;DR: ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, was administered to 11 patients with primary hypercholesterolemia and saw a marked reduction in tuberous xanthomas, but here the drug was less effective in reducing the serum cholesterol level and a higher dose was required for treatment.
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Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals
TL;DR: It is concluded that the lack of hypocholesterolemic activity of ML-236B in mice and rats could, at least partly, be explained by these unexpected results.
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Hypolipidemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase
TL;DR: Serum cholesterol levels were reduced by 44--45% at the higher dosage of 100--400 mg/kg per day but ML-236B caused no significant changes in the cholesterol content of the liver and aorta and in the activities of serum GOT, GPT, CPK and lecithin : cholesterol acyltransferase.
Journal Article
Cholesterol metabolism in man
TL;DR: The recent identification of specific cellular receptors for uptake of plasma lipoproteins represents a significant advance for the understanding of regulation of both plasma and tissue concentrations, and possibly of the basic mechanisms underlying accumulation of cholesterol in atherosclerotic plaques.