Abstract |
The synthesis for the title lactone 2, designed to be an antagonist of the enzyme HMG-CoA reductase (E.C.1.1.1.34), is described. Lactone 2, its synthetic tricyclic hemiacetal precursor 4, and clofibrate were investigated for their antilipidemic activity in 7-day treated normal and in Triton WR-1339 induced hyperlipidemic male Sprague-Dawley rats. After 7-day drug administration to normal rats, lactone 2 was less effective than clofibrate in lowering HMG-CoA reductase activity and serum cholesterol; however, unlike clofibrate, lactone 2 did not increase liver weight or liver- body weight ratio or lower serum triglycerides. Since hemiacetal 4 selectively influenced triglycerides in normal animals, lactone 2 and hemiacetal 4 appear to have differential hypolipidemic effects. In the Triton hyperlipidemic model 2 and 4 lowered elevated triglycerides; only 4 significantly reduced elevated cholesterol levels; but neither 2 nor 4 was as effective as clofibrate. Differences in the observed antilipidemic properties for clofibrate, 2, and 4 in the two animal models are discussed. On the basis of preliminary biological data described in this article it is concluded that tricyclic analogues 2 and 4 represent reasonable leads for the development of new antilipidemic agents.
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Authors | D T Witiak, E Kuwano, D R Feller, J R Baldwin, H A Newman, S K Sankrappa |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 19
Issue 10
Pg. 1214-20
(Oct 1976)
ISSN: 0022-2623 [Print] United States |
PMID | 994152
(Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Hypolipidemic Agents
- Lactones
- Triglycerides
- Cholesterol
- Clofibrate
- Mevalonic Acid
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Topics |
- Animals
- Cholesterol
(blood, metabolism)
- Clofibrate
(analogs & derivatives, chemical synthesis, pharmacology)
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Hyperlipidemias
(blood, metabolism)
- Hypolipidemic Agents
(chemical synthesis)
- Lactones
(chemical synthesis)
- Liver
(enzymology, metabolism)
- Male
- Mevalonic Acid
(analogs & derivatives)
- Rats
- Structure-Activity Relationship
- Triglycerides
(blood, metabolism)
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