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
- 1 September 1994
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 37 (20) , 3240-3246
- https://doi.org/10.1021/jm00046a007
Abstract
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.Keywords
This publication has 0 references indexed in Scilit: