title: Bile acid derived HMG-CoA reductase inhibitors.
abstract: The target organ for HMG-CoA reductase inhibitors to decrease cholesterol biosynthesis in hypercholesterolemic 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 3 xi-(omega-aminoalkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acids to obtain bile acid prodrugs, or 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 microM for the most potent compound S 2467 and 6 microM 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 putative 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 780 and 130 nM for mevinolin. Among the hybrid inhibitors, S 2467 was the most active compound with an IC50-value of 16 microM compared to 55 microM 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.forename: W
authors.initials: W
authors.lastname: Kramer
authors.forename: G
authors.initials: G
authors.lastname: Wess
authors.forename: A
authors.initials: A
authors.lastname: Enhsen
authors.forename: K
authors.initials: K
authors.lastname: Bock
authors.forename: E
authors.initials: E
authors.lastname: Falk
authors.forename: A
authors.initials: A
authors.lastname: Hoffmann
authors.forename: G
authors.initials: G
authors.lastname: Neckermann
authors.forename: D
authors.initials: D
authors.lastname: Gantz
authors.forename: S
authors.initials: S
authors.lastname: Schulz
authors.forename: L
authors.initials: L
authors.lastname: Nickau
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008148:Lovastatin / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011355:Prodrugs; D011725:Pyridines; C062437:HR 780; D008148:Lovastatin