Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids

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 v...

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Veröffentlicht in:	Journal of medicinal chemistry 1990-01, Vol.33 (1), p.52-60
Hauptverfasser:	Beck, G, Kesseler, K, Baader, E, Bartmann, W, Bergmann, A, Granzer, E, Jendralla, H, Von Kerekjarto, B, Krause, R
Format:	Artikel
Sprache:	eng
Schlagworte:	Acetates - metabolism Animals Anticholesteremic Agents Chemical Phenomena Chemistry Cholesterol - biosynthesis Cholesterol - blood Heptanoic Acids - chemical synthesis Heptanoic Acids - pharmacology Hydroxymethylglutaryl-CoA Reductase Inhibitors Lactones - chemical synthesis Lactones - pharmacology Liver - enzymology Liver Neoplasms, Experimental - metabolism Male Molecular Conformation Molecular Structure Pyridines - chemical synthesis Pyridines - pharmacology Pyrimidines - chemical synthesis Pyrimidines - pharmacology Rabbits Rats Structure-Activity Relationship Tumor Cells, Cultured X-Ray Diffraction
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Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00163a010