Abstract
Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.
MeSH terms
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Acetates / metabolism
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Animals
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Anticholesteremic Agents
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Chemical Phenomena
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Chemistry
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Cholesterol / biosynthesis
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Cholesterol / blood
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Heptanoic Acids / chemical synthesis
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Heptanoic Acids / pharmacology*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors*
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Lactones / chemical synthesis
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Lactones / pharmacology*
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Liver / enzymology
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Liver Neoplasms, Experimental / metabolism
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Male
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Molecular Conformation
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Molecular Structure
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Pyridines / chemical synthesis
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Pyridines / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacology*
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Rabbits
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Rats
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Structure-Activity Relationship
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Tumor Cells, Cultured
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X-Ray Diffraction
Substances
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Acetates
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Anticholesteremic Agents
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Lactones
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Pyridines
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Pyrimidines
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HR 780
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Cholesterol