-(METHYLPENTYLAMINO)-PROPYLIDENE-1,1-BISPHOSPHONIC ACID AS A POTENT INHIBITOR OF SQUALENE SYNTHASE

Squalene synthase, the first committed enzyme for sterol synthesis, co nverts farnesyl pyrophosphate to squalene with presqualene pyrophospha te as an intermediate. It was discovered that BM 21.0955 -(methylpenty lamino)-propylidene-1,1-bisphosphonic acid), in development for the tr eatment of bone disorders, inhibited rat liver microsomal squalene syn thase (K-i = 2 nmol/1). BM 21.0955 also inhibited sterol biosynthesis from mevalonate (IC50 = 42 nmol/l), and cholesterol biosynthesis in J7 74 cells (IC50 = 79 mu mol/1). Structural modifications on this molecu le to make it more lipophilic may result in a new class of cholesterol -lowering agents.