Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system.
To increase hepatoselectivity of HMG-CoA reductase inhibitors by using the specific bile acid transport systems, deoxycholic acid-derived inhibitors 9 and 11 have been synthesized, on the basis of the concept of combining in one molecule structural requirements for specific inhibition of the HMG-CoA reductase and specific recognition by the ileal bile acid transport system. The 1-methyl-3-carboxylpropyl subunit of deoxycholic acid was replaced by the 3,5-dihydroxyheptanoic acid lactone of lovastatin, and position 12-OH was esterified with 2-methylbutyric acid. Compounds 9 and 11 were evaluated for their inhibitory activity on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 cells, and [3H]taurocholate uptake in rabbit brush border membrane vesicles and compared with methyl derivatives 8 and 10. The steroidal 21-CH3 group affects both activity on HMG-CoA reductase and recognition by the ileal bile acid transport system.
Wess
G
G
Hoechst AG, Frankfurt am Main, Germany.
Kramer
W
W
Han
X B
XB
Bock
K
K
Enhsen
A
A
Glombik
H
H
Baringhaus
K H
KH
Böger
G
G
Urmann
M
M
Hoffmann
A
A
D000732:Androstanols / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013656:Taurocholic Acid / Q000378:metabolism; D014316:Tritium
D000732:Androstanols; D001647:Bile Acids and Salts; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011753:Pyrones; D014316:Tritium; C089703:2-(2-(3-hydroxy-12-(2-methyl-1-oxobutoxy)-5-androstan-17-yl)ethyl)tetrahydro-4-hydroxy-2H-pyran-6-one; D013656:Taurocholic Acid; D002784:Cholesterol; D012964:Sodium