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 in hibitors 9 and 11 have been synthesized, on the basis of the concept o f combining in one molecule structural requirements for specific inhib ition of the HMG-CoA reductase and specific recognition by the ileal b ile acid transport system. The 1-methyl-3-carboxylpropyl subunit of de oxycholic acid was replaced by the 3,5-dihydroxy-heptanoic acid lacton e of lovastatin, and position 12-OH was esterified with 2-methylbutyri c acid. Compounds 9 and 11 were evaluated for their inhibitory activit y on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 c ells, and [H-3]taurocholate uptake in rabbit brush border membrane ves icles and compared with methyl derivatives 8 and 10. The steroidal 21- CH3 group affects both activity on HMG-CoA reductase and recognition b y the ileal bile acid transport system.