The long range objective of this project is to prepare and evaluate potential dual action inhibitors of cholesterol biosynthesis. These compounds were designed as inhibitors of lanosterol 14alpha-methyl demethylase (P-45ODM) and as supressors of HMG-CoA reductase (HMGR) activity. P-45ODM is the cytochrome P-450 monooxygenase which oxidatively removes the 14alpha-methyl group of lanosterol. This demethylation is the rate limiting step in the conversion of lanosterol to cholesterol. The intermediates in this transformation have been implicated in the regulation of HMGR synthesis. HMGR is the rate limiting enzyme in overall cholesterol biosynthesis. The proposed compounds will be synthesized and their inhibitory and binding properties towards P-450DM will be carried out in the laboratory of the principal investigator. Studies of their effects on sterol synthesis and HMGR levels in L cell cultures will be done in collaboration with Dr. Andrew A. Kandutsch (Jackson Laboratory). The study of the proposed lanosterol analogs will provide important information about the mechanism and active site of P-450 DM along with a better understanding of the processes by which the natural intermediates generated by P-450DM regulate HMGR activity. In addition, it is possible that a compound will be obtained with significantly in vivo antihypercholesterolemic activity.
| Frye, L L; Leonard, D A (1999) Lanosterol analogs: dual-action inhibitors of cholesterol biosynthesis. Crit Rev Biochem Mol Biol 34:123-40 |
| Anderson, J A; Leonard, D A; Cusack, K P et al. (1995) 15-substituted lanosterols: post-transcriptional suppressors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Arch Biochem Biophys 316:190-6 |
| Frye, L L; Cusack, K P; Leonard, D A et al. (1994) Oxolanosterol oximes: dual-action inhibitors of cholesterol biosynthesis. J Lipid Res 35:1333-44 |
| Frye, L L; Cusack, K P; Leonard, D A (1993) 32-Methyl-32-oxylanosterols: dual-action inhibitors of cholesterol biosynthesis. J Med Chem 36:410-6 |
