Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Hydroxamic Acids/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4 , Fibroblasts/enzymology , Gelatinases/antagonists & inhibitors , Guinea Pigs , Hydroxamic Acids/pharmacology , Macrophages/enzymology , Matrix Metalloproteinase 1 , Matrix Metalloproteinase 2 , Matrix Metalloproteinase Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Sulfones/pharmacologyABSTRACT
Some bisphosphonates used for the treatment of bone disorders are also potent inhibitors of squalene synthase, a critical enzyme for sterol biosynthesis. Among seven drugs tested, YM 175 (cycloheptylaminomethylene-1,1-bisphosphonic acid) was the most potent inhibitor of rat liver microsomal squalene synthase (Ki = 57 nM) and sterol biosynthesis from [14C]mevalonate in rat liver homogenate (IC50 = 17 nM). EB 1053 (3-(1-pyrolidino)-1-hydroxypropylidene-1,1-bisphosphonic acid) and PHPBP (3-(1-piperidino)-1-hydroxypropylidene-1,1-bisphosphonic acid) were less potent inhibitors in both these assays. Pamidronate and alendronate were poor inhibitors of squalene synthase (IC50 > 10 microM) but were potent inhibitors of sterol biosynthesis from mevalonate (IC50 = 420 and 168 nM, respectively), suggesting that the latter two agents may have inhibited other enzymes involved in the synthesis of farnesyl pyrophosphate from mevalonate. Etidronate and clodronate were inactive in both these assays. YM 175 also inhibited sterol biosynthesis in mouse macrophage J774 cells (IC50 = 64 microM) and in rats, when administered acutely, it inhibited cholesterol biosynthesis in the liver (ED50 = 30 mg/kg, s.c.). Structural modifications on YM 175 to enhance cell permeability may result in a new class of cholesterol-lowering agents.
