Bile acid derived HMG-CoA reductase inhibitors

Werner Kramer, Günther Wess, Alfons Enhsen, Klaus Bock, Eugen Falk, Axel Hoffman, Georg Neckermann, Dietrich Gantz, Siefried Schulz, Lutz Nickau, Ernst Petzinger, Stephen Turley, John M. Dietschy

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


The target organ for HMG-CoA reductase inhibitors to decrease cholesterol biosynthesis in hypercholosterolemic patients is the liver. Since bile acids undergo an enterohepatic circulation showing a strict organotropism for the liver and the small intestine, the structural elements of an inhibitor for HMG-CoA reductase were combined with those for specific molecular recognition of a bile acid molecule for selective uptake by hepatocytes. Either, the HMG-CoA reductase inhibitors HR 780 and mevinolin were covalently attached to 3ξ-(ω-aminoalkoxy)-7α, 12 α-dihydroxy-5 β-cholan-24-oic acids to obtaine bile acid prodrugs, of the side chain of bile acids at C-17 was replaced by 3,5-dihydroxy-heptanoic acid - a structural element essential for inhibition of HMG-CoA reductase - to obtain hybrid bile acid: HMG-CoA reductase inhibitors. The prodrugs could, as expected, not inhibit rat liver HMG-CoA reductase to a significant extent, whereas the hybrid inhibitors showed a stereospecific inhibition of HMG-CoA reductase from rat liver microsomes with an IC50-value of 0.7 μM for the most potent compound S 2467 and 6 μM for its diastereomere S 2468. Uptake measurements with isolated rat hepatocytes and ileal brush-border membrane vesicles from rabbit small intestine revealed a specific interaction of both classes of bile acid-derived HMG-CoA reductase inhibitors with the hepatocyte and ileocyte bile acid uptake systems. Photoaffinity labeling studies using 3-azi- or 7-azi-derivatives of taurocholate with freshly isolated rat hepatocytes or rabbit ileal brush-border membrane vesicles revealed a specific interaction of bile acid derived HMG-CoA reductase inhibitors with the respective putatative bile acid transporters in the liver and the ileum demonstrating the bile acid character of these derivatives, both for the prodrugs and the hybrids. Cholesterol biosynthesis in Hep G2 cells was inhibited by the bile acid prodrugs with IC50-values in the range of 68 nM to 600 nM compared to 13 nM for HR 78 and 130 nM for mevinolin. Among the hybrid inhibitors, S 2467 was the most active compound with an IC50-value of 16 μM compared to 55 μM for its diastereomere S 2468. Preliminary in vivo experiments showed an inhibition of hepatic cholesterol biosynthesis after oral dosage only with prodrugs such as S 3554, whereas the hybrid molecules were inactive after oral application. Measurement of inhibition of cholesterol biosynthesis by incorporation of [14C]octanoate or [3H]H2O into the digitonin-precipitable sterol fraction in the liver and extrahepatic organs demonstrated a significant increase of liver selectivity of HMG-CoA reductase inhibitors such as HR 780 by coupling to bile acids. Taken together, these studies demonstrate that the liver selectivity of an HMG-CoA reductase inhibitor can be increased by combining with bile acid structural elements and making use of specific bile acid transport pathways of the liver.

Original languageEnglish (US)
Pages (from-to)137-154
Number of pages18
JournalBBA - Molecular Basis of Disease
Issue number3
StatePublished - Nov 29 1994


  • Bile acid transport
  • Drug delivery
  • Drug targeting
  • HMG-CoA reductase inhibitor
  • Liver specificity
  • Photoaffinity labeling

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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