1-hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase

Squalene synthase, the first committed enzyme for sterol synthesis, converts farnesyl pyrophosphate to squalene with presqualene pyrophosphate as an intermediate. It was discovered that BM 21.0955 (1-hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid), in development for the treatment of bone disorders, inhibited rat liver microsomal squalene synthase (K-i = 2 nmol/1). BM 21.0955 also inhibited sterol biosynthesis from mevalonate (IC50 = 42 nmol/l), and cholesterol biosynthesis in J774 cells (IC50 = 79 mu mol/1). Structural modifications on this molecule to make it more lipophilic may result in a new class of cholesterol-lowering agents.