ABSTRACT
A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.
Subject(s)
Anticholesteremic Agents/pharmacology , Caproates/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lactones/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Caproates/chemical synthesis , Carcinoma, Hepatocellular/enzymology , Cholesterol/biosynthesis , Cholesterol/blood , Dogs , Humans , Lactones/chemical synthesis , Liver/enzymology , Liver Neoplasms/enzymology , Lovastatin/pharmacology , Male , Molecular Structure , Rabbits , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lactones/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Acetates/metabolism , Animals , Anticholesteremic Agents , Chemical Phenomena , Chemistry , Cholesterol/biosynthesis , Cholesterol/blood , Heptanoic Acids/chemical synthesis , Lactones/chemical synthesis , Liver/enzymology , Liver Neoplasms, Experimental/metabolism , Male , Molecular Conformation , Molecular Structure , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Rabbits , Rats , Structure-Activity Relationship , Tumor Cells, Cultured , X-Ray DiffractionABSTRACT
A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.
