Abstract
Administration (p.o.) of SKP-450, 2-[2"-(1",3"-dioxolane)]-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H- 1-benzopyran, a novel antihypertensive agent, to hypercholesterolemic Syrian hamsters led to a significant reduction in plasma lipids in a dose-dependent manner, i.e., a 10.8% to 29% reduction in low-density lipoprotein cholesterol at doses of 0.3 to 10 mg/kg of SKP-450. SKP-450 was found to specifically inhibit the hepatic microsomal lanosterol 14alpha-methyl demethylase (14alpha-DM) in a competitive manner (Ki:2.65 microM). Furthermore, a dose-dependent decrease in the 14alpha-DM activity by SKP-450 parallelled the cholesterol synthetic rate in vitro in both the rat hepatic S10 fractions (supernatants at 10,000 g; IC50:20 microM) and Chinese hamster ovary cells (IC50:23 microM). However, this phenomenon was not seen in AR45 cells, which are deficient in 14alpha-DM, suggesting that 14alpha-DM is the major target for the inhibitory action of SKP-450 in regard to cholesterol biosynthesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticholesteremic Agents / administration & dosage
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Anticholesteremic Agents / pharmacology*
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Antihypertensive Agents / administration & dosage
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Antihypertensive Agents / pharmacology*
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Benzopyrans / administration & dosage
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Benzopyrans / pharmacology*
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Binding, Competitive
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CHO Cells
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Cholesterol, LDL / blood
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Cricetinae
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism*
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Dose-Response Relationship, Drug
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Hypercholesterolemia / blood
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Hypercholesterolemia / drug therapy*
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Kinetics
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Mesocricetus
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Microsomes, Liver / enzymology*
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Oxidoreductases / antagonists & inhibitors
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Oxidoreductases / metabolism*
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Pyrrolidinones / administration & dosage
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Pyrrolidinones / pharmacology*
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Rats
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Sterol 14-Demethylase
Substances
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Anticholesteremic Agents
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Antihypertensive Agents
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Benzopyrans
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Cholesterol, LDL
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Cyp51 protein, rat
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Cytochrome P-450 Enzyme Inhibitors
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Pyrrolidinones
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KR 30450
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Cytochrome P-450 Enzyme System
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Oxidoreductases
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Sterol 14-Demethylase