LIPOPHILIC 1,1-BISPHOSPHONATES ARE POTENT SQUALENE SYNTHASE INHIBITORS AND ORALLY-ACTIVE CHOLESTEROL-LOWERING AGENTS IN-VIVO

Squalene synthase catalyzes the reductive dimerization of two molecule s of farnesyl diphosphate to form squalene at the final branchpoint of the cholesterol biosynthetic pathway. We report herein that isoprenyl 1,1-bisphosphonates and related analogs are potent inhibitors of rat microsomal squalene synthase (I50 = 0.7-32 nM). In addition, members o f this family are potent inhibitors of cholesterol biosynthesis in rat s on intravenous and oral dosing, as well as cholesterol lowering agen ts in rats and hamsters. Significant inhibition of cholesterol biosynt hesis in rats by lovastatin occurs with a concomitant inhibition of do lichol and coenzyme-Q9 synthesis. In contrast, bisphosphonate 4 has no effect on dolichol and coenzyme-Q9 biosynthesis in rats under conditi ons where cholesterol biosynthesis is >90% inhibited.